Key words
adrenal insufficiency - glucocorticoid replacement - adrenal crisis - emergency card - diagnostic criteria
Introduction
Adrenal crisis is a potentially life-threatening complication in patients with
adrenal insufficiency. It can occur when an acutely increased cortisol demand is not
met by adequate cortisol supply. Inappropriate glucocorticoid adjustment in
gastrointestinal or febrile infections, surgical procedures, intensive physical
activity, major psychological or social stress and, occasionally, a so far
undiagnosed adrenal insufficiency are common triggers of an adrenal crisis [1]. Several studies demonstrated a higher risk
for adrenal crises as formerly assumed. A 2-year prospective follow-up of more than
400 patients with adrenal insufficiency detected a prevalence of 8.3 adrenal crises
per 100 patient years [2]. Life-time risk of
adrenal crisis was calculated at about 50% [3]. Patients with primary adrenal insufficiency are at higher risk than
patients with secondary adrenal insufficiency with prevalence rates of 7.6 vs. 3.2
per 100 patient years as reported in a retrospective study [4].
Excess mortality has been shown in patients with primary [5]
[6] as
well as secondary adrenal insufficiency [7].
Adrenal crises substantially contribute to this excess mortality [8]. A large Swedish study demonstrated that
42% of all deaths among patients with congenital adrenal hyperplasia were
due to adrenal crisis [9]. In the prospective
study mentioned above, mortality of adrenal crisis was 6.3% [2]. It can therefore be concluded that 1 out of
200 adrenal insufficient patients will die from an adrenal crisis per year, whereby
regional differences may exist. For Germany, a prevalence for adrenal insufficiency
of about 348 per million has been determined, thereof 222 per million for secondary
and 126 per million for primary adrenal insufficiency [4].
Based on these data, a total number of about 29 000 patients with adrenal
insufficiency can be calculated for Germany, and about 1500 fatalities due to
adrenal crises have to be expected within the next decade. Since there are measures
to prevent and treat an adrenal crisis, this projection is deplorable and
alarming.
In the last decade, several projects were carried out to improve prevention as well
as awareness and treatment of adrenal crises. A standardized, pan-European emergency
card for patients with adrenal insufficiency was introduced in 2014 by modifying the
original Swedish emergency card [10]
[11]
[12].
This European Emergency card in a credit card format is nowadays available in
multiple languages. The card bears an English text on one side and the same text in
the patient’s native language on the other. In the same year, the German
Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie, DGE)
developed and implemented a nation-wide structured and certified educational program
for patients with adrenal insufficiency and their relatives [13]. Beyond that, structured training programs
and written information for medical staff and paramedics were developed or updated,
respectively.
Despite these efforts, management of adrenal crises is still unsatisfactory. A German
retrospective analysis demonstrated a delay above an accepted time limit between
declaration of symptoms suspicious for an adrenal crisis and initiation of
parenteral glucocorticoid treatment in over 40% of patients [14]. It has to be assumed that comparable
outcome data could also be observed elsewhere in Europe.
The objectives of this study were to establish consensus for diagnostic criteria,
prevention strategies, and treatment recommendations for adrenal crises, with the
aim that in ten years no one will die from an adrenal crisis anymore.
Materials and Methods
Delphi technique was used for this consensus analysis [15]. This method uses a series of
questionnaires sent to participants who were selected for their expertise in the
management of adrenal insufficiency and adrenal crisis by a coordinating group (TD,
SH, JH, MK, MQ, NR, NR, HSW, TK, GM) on behalf of the “Section for adrenal,
steroids and hypertension” of the German Society of Endocrinology (Sektion
Nebenniere, Steroide und Hypertonie der DGE). The process included 45 experts from
32 centers, including in the majority endocrinologists, but also intensive care
physicians (n=7), pediatric endocrinologists (n=4), endocrine nurses
and patient voices (n=2), neurosurgeons (n=2), endocrine surgeons
(n=1), as well as laboratory physicians (n=1).
In total, this Delphi process required four rounds of questionnaires to reach an
adequate consensus. First round of the survey comprised five group of themes
(definition of adrenal crisis, current deficits, management by medical staff,
measures of self-management by patients, future projects), including 20 items in
total. In the second round, experts received a summary of the answers and comments
provided in the first round, requesting their review. Third round enfolded a
compilation of questions based on panelists’ comments and eight adapted
questions about topics where a consent could not be achieved by then. In the fourth
round, four final items were forwarded, each regarding still pending consensus.
The survey was implemented online using REDCap, a secure web application for building
and managing online surveys [16]. Responses
were captured anonymously. Replies were monitored by two coordination group members
(TK and GM). The study was conducted from January 2022 to April 2023. Response rates
reached 78% in the first round, 55% in the second, 53% in
the third and 58% in the final round of the survey.
Results
Definition of adrenal crisis
Experts agreed that objective criteria need to be identified that help patients,
their families and medical staff to recognize adrenal crises (96%
agreement in first round of questionnaire). To define adrenal crisis the
criteria established by Allolio in 2015 were suggested [17]. According to this definition, an
adrenal crisis is a major impairment of general health with at least two of the
following signs/symptoms: arterial hypotension (systolic blood
pressure<100 mmHg), nausea or vomiting, severe fatigue, fever,
somnolence, hyponatremia (≤132 mmol/l) or hyperkalemia,
and/or hypoglycemia. In addition, parenteral glucocorticoid (usually
hydrocortisone) must be administered, followed by clinical improvement. Although
86% of experts agreed with this definition in the first round of the
questionnaire, numerous comments were raised demanding a further specification
of this definition. Therefore, a different definition based on the
experts’ suggestions was developed ([Table 1]). In addition, experts were reminded to base their decision
on the intention to help non-endocrinologists, medical staff and emergency
personnel not experienced with adrenal insufficiency and unsure about
administration of glucocorticoids in case of an adrenal crisis. Keeping this
goal in mind, in the final round of the questionnaire 65% of experts
preferred the revised definition in comparison to the definition by Allolio
(35%).
Table 1 Definition of adrenal crisis.
|
Adrenal crisis must be considered if≥1 type A
criterion and≥2 type B criteria can be applied:
|
|
Type A criteria:
|
|
|
|
Type B criteria:
|
|
|
Current deficits
Without doubt, according to experts there is no sufficient access for patients
and their families to structured education programs (agreement of 82%).
While most centers also do not have enough time for educating and instructing
patients about adrenal insufficiency (73% agreement), most of the
experts estimate more than 60% of their patients to be appropriately
educated about their disease and emergency measures (61–80% of
patients in 38% of experts’ practices/clinics;
81–100% of patients in 19% of experts’
practices/clinics). However, in 29% of the experts’
working institutions only 41–60% of patients are estimated to be
educated well, and 14% of the experts estimated that only
21–40% of their adrenal insufficient patients know about their
disease and emergency measures. Importantly, while some experts work in the same
institution, there may still be a different education level of the patients
under their supervision. Therefore, subgroup differentiation was made per expert
if several experts came from the same institution.
All experts agreed that patients with a diagnosis of adrenal insufficiency should
be identifiable at any time by medical personnel (i. e., by a
tag/note in an electronic patient record). They also believed that the
European emergency card in its current form and content is sufficiently known
(91%). However, 29% of experts believe that the European
emergency card for adrenal insufficiency in its current form and content is not
appropriate to improve emergency management. In the third round of the
questionnaire, we therefore suggested according to the annotations of several
experts, that the European emergency card should include a QR code with a link
that provides information about treatment of adrenal crisis which 91% of
experts considered to be a valuable improvement. A majority (52%)
preferred the QR link to guide the user to the website of the German Society of
Endocrinology, 29% favored a website of the European Society of
Endocrinology.
Management of adrenal insufficiency by medical staff
For improvement of adrenal crisis emergency management education of emergency
personnel and paramedics was considered to have highest priority (91%).
Installing common standard operating procedures (SOPs) for download on the
website of a (national) professional society was rated to be important, too
(86% categorized the latter measure as second highest priority). In
comparison, having national or regional consulting services for endocrine
emergencies (similar to poison control centers) and establishing specialized
centers for endocrine emergencies (like a Chest Pain Unit) have minor priority
according to experts (third priority for consulting services in 81% and
lowest priority for endocrine emergency centers in 81%).
There is consent that each surgical center, which performs adrenalectomies should
locally establish an interdisciplinary SOP for perioperative management in these
patients (100%). Furthermore, following pituitary surgery or
radiotherapy, every patient should see a physician experienced in diagnosing
adrenal insufficiency and also undergo a postinterventional dynamic stimulation
test of the adrenal axis (within 3–6 months after surgery) for
confirmation or exclusion of adrenal insufficiency (95% agreement).
Also, after an adrenal crisis, every patient should be seen by a physician
experienced in diagnosing and educating patients on adrenal insufficiency
(95% agreement).
With respect to the management of febrile episodes occurring at home (sick day
rule 1), experts regarded doubling (if fever>38 °C) or tripling
(if fever>39 °C) of oral glucocorticoid until recovery (usually
after 2–3 days) as appropriate (95% agreement). If a patient is
unable to tolerate oral medication (e. g., due to vomiting
and/or diarrhea, trauma, high fever, or clinical deterioration) (sick
day rule 2), 100 mg hydrocortisone should be given parenteral
(i. e., intramuscular or subcutaneous (the latter off-label)) and health
professionals should be contacted in case of initial self-treatment (91%
agreement).
There was consent on current recommendations about management of acute adrenal
crisis (90% agreement in second round of questionnaires): Patients
should receive sufficient intravenous volume replacement and 100 mg
hydrocortisone as an intravenous bolus injection followed by 200 mg
hydrocortisone as a continuous infusion over 24 hours (for children dose
adjustment according to body weight or body surface area). If hydrocortisone is
not available, alternative glucocorticoids (i. e., prednisolone in a
dosage of at least 25 mg) can be used for emergency treatment of acute
adrenal crisis (agreement of 86% to add this information in guidelines).
In major surgery with general anesthesia, trauma, delivery, or disease that
requires intensive care, 100 mg hydrocortisone as intravenous injection
followed by continuous intravenous infusion of 200 mg hydrocortisone
over 24 hours should be given (agreement of 91% in second round
of questionnaires). A large number of comments addressed the need for a more
liberal approach to dosages of glucocorticoids in adrenal crisis. Therefore, in
the final round of questionnaires there was consent that in patients with a
longer history of adrenal insufficiency experienced physicians may suggest lower
doses (in case of an adrenal crisis and major surgery) according to individual
patient needs. This is also true for minor or moderate surgical stress where
100 mg hydrocortisone as an intravenous bolus should be given with the
beginning of anesthesia (96% agreement). In minor surgical stress in
local anesthesia (i. e., dermatological or dental procedures) doubling
of usual oral glucocorticoid dosage is considered to be appropriate
(100% agreement in third round of questionnaires). [Table 2] summarizes recommendations
arising from this Delphi survey.
Table 2 Management of adrenal crisis and risk
situations.
|
Management of an acute adrenal crisis
|
Sufficient intravenous volume replacement and 100 mg
hydrocortisone as an intravenous bolus injection followed by
200 mg as a continuous infusion over
24 h*# (for children dose
adjustment according to body weight or body surface
area)
|
|
Major surgery with general anesthesia, trauma, delivery or
disease that requires intensive care
|
100 mg hydrocortisone as intravenous injection
followed by continuous intravenous infusion of
200 mg over 24 h*#
|
|
Minor or moderate surgical stress
|
100 mg hydrocortisone as an intravenous bolus given
with the beginning of anesthesia*#
|
|
Minor surgical stress in local anesthesia (i. e.,
dermatological or dental procedures)
|
Doubling of usual oral glucocorticoid dosage
|
|
Management of illness with fever at home (sick day rule
1)
|
Doubling (if fever>38 °C) or tripling (if
fever>39 °C) of oral hydrocortisone
replacement dosing until recovery (usually after 2–3
days)
|
|
Inability to tolerate oral medication (vomiting
and/or diarrhea, trauma, high fever and clinical
deterioration) (sick day rule 2)
|
100 mg parenteral hydrocortisone; contacting health
professionals in case of initial
self-treatment#
|
* In patients with a longer history of adrenal
insufficiency experienced physicians may suggest lower doses according
to individual patient needs.; # If hydrocortisone is not
available, alternative glucocorticoids (i. e., prednisolone in a
dosage of at least 25 mg) can be used for emergency treatment of
acute adrenal crisis.
Measures for self-management of adrenal insufficiency and crisis
All patients with adrenal insufficiency have to be equipped with a standardized
glucocorticoid emergency card and prescription for an additional supply of oral
glucocorticoids as well as a hydrocortisone self-injection kit for emergency
management (100%). All patients have to be educated in recognizing signs
and symptoms of an adrenal crisis and in correct management of emergency events
(sick day rules, training in hydrocortisone emergency self-injection
(100%).
Bi-annual repetition of patient education was regarded unrealistic or
inappropriate by 48% of experts. Therefore, experts agreed that
repetition of patient education at least once yearly is a treatment goal
(74% agreement).
Future projects
Experts were asked about the relevance of a (possibly mandatory) registry for the
occurrence of adrenal crises in Germany/Europe to identify details in a
structured manner (i. e., triggering factors, acute symptoms, latency
from first symptoms until first contact with a physician or administration of
glucocorticoids, convalescence). On a scale from 1 to 5, 20% considered
such a platform as highly relevant (scale value 5; 36% for 4,
20% for 3 and 24% for 2). However, most experts would actively
support such a registry (92%).
Discussion
During the last years progress has been made in treatment and management of patients
with adrenal insufficiency. Educational programs for patients and their families
[13] as well as emergency equipment for
situations with increased cortisol demand have contributed to this positive trend.
However, adrenal crisis is still a major cause of death in patients with adrenal
insufficiency and must not be missed [2]. Even
more importantly, adrenal crisis can be prevented in many cases.
The Delphi technique used in the process of this survey has certain limitations as it
represents the opinion of selected experts in the field. However, in rare diseases
it needs experts to identify shortcomings of current patient care.
Despite guidelines on adrenal insufficiency [17]
[18]
[19]
[20],
especially non-endocrinologists are often unsure about diagnosis of adrenal crisis,
even when confronted with emergency cards about adrenal insufficiency from patients
or the patients’ relatives. Since most physicians and emergency personnel
rarely encounter an adrenal crisis, there is a high risk it can be overlooked. In
addition, there is often doubt about administration of glucocorticoids in situations
where an infection can be the underlying cause of an adrenal crisis [21]. In fact, stress doses of short acting
glucocorticoids (i. e., hydrocortisone or prednisolone) administered
short-term, are not known to lead to relevant adverse events [20], but can be life-saving.
In 2015, Allolio suggested a definition of adrenal crisis that does not only address
signs and symptoms of a crisis, but also demands parenteral glucocorticoid
administration followed by clinical improvement [17]. The definition was developed from a scientific objective to
investigate the incidence of adrenal crises prospectively [2]. Until then, no clear definition of adrenal
crisis had been made, making research in this field difficult.
A large majority of our experts agreed with the definition by Allolio in our Delphi
survey, but not without pointing out the definition’s pitfalls. For
scientific questions, a clear definition of what is regarded as adrenal crisis is
important. Establishing a clear definition in this regard is challenging per se.
Based on published definitions, for example, patients who died of a crisis because
no glucocorticoid was administered would not be counted, while patients who
generously administered parenteral glucocorticoid for fear of a crisis would be
counted. In the clinical setting, the definition of adrenal crisis seems less
relevant than the identification of situations that pose a threat to patients with
adrenal insufficiency and require appropriate action to prevent a severe course.
After reminding the experts that goal of this definition must be to not miss any
adrenal crisis, two thirds of experts preferred our newly proposed definition
compared to the original definition by Allolio ([Table 1]). Its intention is to categorize situations where adrenal crisis
is likely or very likely and where glucocorticoid administration must not be
delayed. However, when a patient fails to improve, other causes of the clinical
picture need to be considered. In contrast, for scientific objectives the definition
by Allolio might be a more conclusive tool. Prospective studies will be needed to
evaluate the value of our newly proposed definition in diagnosis of adrenal crisis
and improvement of outcome.
There is no doubt that education of patients and their relatives is essential to
prevent adrenal crises [13]. It empowers
patients and families to act adequately in case of an impending adrenal crisis even
when far away from an endocrine center. Patients need to be equipped with an
emergency card (national and or international version) and with emergency medication
such as glucocorticoid suppositories and/or glucocorticoid ampules [1].
During the last decade a structured nationwide educational program for patients with
adrenal insufficiency has been established in Germany [13]. Today, this program is certified by the
German Society of Endocrinology and is offered by more than 70 endocrine centers.
Nevertheless, in the experts’ opinion there is still a large discrepancy
between the obvious need for patient education and its availability. While
endocrinologists undertake considerable efforts to educate their patients,
43% of the experts estimated that only 21–60% of their
patients have a good knowledge about their disease and emergency measures. This fits
well with studies investigating into knowledge of patients who receive treatment at
specialized centers [13]
[22]
[23].
Of course, our expert panel also included specialties that may not have direct and
regular contact with adrenal insufficient patients or take part in education
programs (i. e., laboratory medicine, intensive care medicine). However,
only 9% of participants in the anonymous questionnaire declared not to be an
endocrinologist. 72% of experts work in a university hospital or clinic and
32% in an outpatient clinic. Importantly, 96% of experts who
answered the questionnaire declared that a structured patient training takes place
in their center. Keeping this in mind, it is highly relevant that in most centers
there is not enough time and resources for instructing and educating patients. One
underlying reason may be that time and effort for educational programs in adrenal
insufficiency is still not reimbursed by insurances in Germany, unlike for diabetes
educational programs, for example. Accordingly, a biannual education of patients in
recognizing adrenal crisis and acting appropriately seems too ambitious and may not
be needed in all patients. An annual repetition is recommended, though.
For improvement of emergency management of adrenal insufficiency, it seems to be of
upmost priority to involve emergency staff and paramedics in order to broaden
knowledge about adrenal crisis. While the European emergency card is sufficiently
known, one third of our experts has doubts about its role in improving emergency
management. Currently, it gives basic instructions for glucocorticoid stress dosing
in case of an adrenal crisis, but does not provide further information on diagnosis
of an adrenal crisis or management of situations with increased cortisol demand and
risk to develop into a crisis [12]. In
comparison, this information is given in the current form of the national emergency
card by the German Society of Endocrinology [24]
[25]. That is why a QR code
implemented on the European emergency card and leading to official guidelines from
the national Society of Endocrinology as suggested by our expert panel might add to
the quality of emergency management of adrenal insufficiency. This could be of
benefit especially in situations where medical staff not experienced with adrenal
insufficiency is involved and simplified instructions are needed.
Instead of focusing on specialized centers that treat endocrine emergencies, experts
generally agree that knowledge about adrenal insufficiency has to be spread widely
in order to decrease mortality from adrenal crisis. In this light, there was a
lively discussion during the Delphi process of how to simplify instructions for
non-endocrinologists while still allowing individual approaches for patients and
physicians that are experienced with the disease.
All patients with a history of adrenal crisis and after surgery or radiotherapy of
the pituitary should be seen by a physician that is experienced with adrenal
insufficiency and followed-up. In management of adrenal crisis, surgery that
requires general anesthesia, trauma or delivery our expert panel largely agrees with
current recommendations ([Table 2]) [17]
[18].
In minor surgical procedures that require only local anesthesia (such as dental or
dermatological interventions) doubling of the usual oral glucocorticoid dosage is
recommended. However, for patients with a long history of adrenal insufficiency and
physicians very experienced with their patients’ course of the disease,
alternative doses may be recommended individually.
Conclusion
From this study diagnostic criteria have been developed to identify patients likely
to have an adrenal crisis and to allow immediate initiation of emergency measures.
Emergency management needs to be simplified in order to be applied by a broad field
of national and international medical personnel as well as patients themselves.
Recommendations and instructions evolving from our Delphi survey aim to be a
pragmatic tool to recognize emergency situations and act appropriately. This will
hopefully add to our declared goal that no more patients must die from an adrenal
crisis.
