Background
The long-term management of patients with adrenal insufficiency (AI) is a challenge
in several respects. Increased morbidity and mortality and reduced quality of life
together with impairments in work-life and leisure activities have been documented.
With normal function, the adrenal gland is a very dynamic organ that responds
quickly to an increased need for corticosteroids. Sufficient supply of
glucocorticoids to the body is vital. It is also highly relevant for the management
of everyday tasks and the maintenance of general performance. Over- or
under-substitution carries the risk of increased morbidity in the form of side
effects or adrenal crises. While other diseases are treated with constant
medication, AI often requires fast action with situational dose adaptation. Reduced
quality of life may in part be optimized by an improved dose regimen, but also an
improved knowledge of the disease and of possible options for action by the patient.
The rarity of the disease in combination with the need to respond to stressful
situations with rapid glucocorticoid dose adjustment underlines that a well-educated
patient is crucial for optimal management of the disease.
Patient’s education should fulfill several aims: a) to provide a better
understanding of the illness and to increase quality of life; b) to reduce
morbidities and increase long-term outcome through optimized dose adaptation and
avoidance of over- or under-substitution; c) to reduce mortality by preventing
adrenal crisis (AC).
In the following paragraph we provide background information further clarifying the
need of education in patients with AI.
Mortality
Recent studies revealed increased mortality in chronic AI patients [1]
[2]
[3]
[4]
[5]. A study analyzing the National
Swedish Hospital and Cause of Death Registry showed an increased mortality in
patients with Addison's disease (2.2-fold for men and 2.9-fold for
women) compared to normative data [6]. Especially the mortality due to infectious diseases was greatly
increased (6.6-fold in men and 5.6-fold in women) [6]. This data is endorsed by a study
from the Netherlands showing an increased incidence of infectious disease in
Addison’s disease [7].
But also in patients with secondary AI the standardized mortality ratio is
increased up to 3.5-fold in men and 4.5-fold in women, as analyzed in a review
by Sherlock et al. [3]. A Swedish
study with 755 patients with secondary AI described an even higher standard
mortality ratio for death from infectious disease of 8.9-fold [2]. This data suggests that patients
with chronic AI are particularly threatened by infectious disease and that AC
substantially contributes to the increased mortality in secondary AI. The most
common form of AI is iatrogenic AI due to immuno-suppressive, or -modulatory
glucocorticoid doses, or as side effect of a checkpoint-inhibition therapy. The
underdiagnosis and underrecording of adrenal dysfunction in those patients is
common in clinical practice and leads to a high mortality [8].
Several studies in secondary AI indicate that high hydrocortisone doses as
glucocorticoid replacement therapy are associated with an increased mortality.
This was demonstrated in 178 acromegalic patients with secondary AI [9], where daily hydrocortisone doses
above 25 mg significantly increased mortality. This finding was supported by an
analysis in 105 patients with non-secreting pituitary adenoma and secondary AI
[10] showing a 4-fold increase in
total mortality for daily hydrocortisone doses above 30 mg. It is assumed that
increased daily hydrocortisone doses lead to higher cardiovascular risk factors,
thus resulting in higher death rates from vascular disorders in patients with
hypopituitarism [11]. A recent study
from England, Netherlands and Denmark confirmed this finding demonstrating that
patients taking a glucocorticoid treatment had a 2-fold increased standard
mortality ratio compared to the general population, whereas patients without
daily glucocorticoids were not different to the general population [12]. Furthermore, data from the
European Adrenal Insufficiency Registry showed that especially older, male
patients with secondary AI and with hypertension and diabetes mellitus receiving
higher hydrocortisone doses had a higher mortality risk [13]. Even daily doses of 30 mg
of daily hydrocortisone showed a much more unfavorable blood pressure profile
compared to doses of 15 or 20 mg hydrocortisone potentially contributing
to the observed excess mortality [14]
[15].
Adrenal crisis
Adrenal crisis (AC) is a life-threatening emergency that may occur in patients
with chronic AI and is in part responsible for the increased mortality [16]
[17]
[18]
[19]
[20]. A clear definition of AC is
difficult and varies among studies, contributing to varying numbers and causes
of AC. Allolio defined AC [21] as
profound impairment of general health and at least two of the following
conditions: hypotension (systolic blood pressure <100 mmHg), nausea or
vomiting, severe fatigue, hyponatremia, hypoglycemia and hyperkalemia,
triggering subsequent parenteral glucocorticoid administration. Even if AC is
recognized and treated accordingly it is associated with a high mortality of
6.3% [22] suggesting that if
not recognized and correctly treated, it is responsible for a large percentage
of deaths among AI patients [2]
[5]. In a Norwegian analysis,
“adrenal failure” was the second most frequent cause of death
(15%) in patients with Addison’s disease [1].
Precipitating factors for AC are stressful conditions leading to an increased
glucocorticoid demand like infectious disease (especially gastroenteritis and
other infectious diseases), trauma, surgery, but also psychological distress
(mental or emotional stress), strenuous physical activity, as well as changes in
glucocorticoid replacement therapy [7]
[17]
[18]
[22]. Thus, it is of high importance
that patients with AI adjust their glucocorticoid dose under stressful
conditions to prevent AC.
In a retrospective study from Germany the frequency of AC was measured with 6.6
crises per 100 patient years in primary AI and 5.8 crises per 100 patient years
in secondary AI [18]. Retrospective
data from the Netherlands revealed similar data (5.2 crises in primary AI and
3.6 crises in secondary AI per 100 patient years) [7]. Data from the UK Addison disease
self-help group showed a higher AC rate with 8 crises per 100 patient years in
primary AI [17]. The only prospective
AC study revealed an even higher frequency with 64 ACs in 767.5 patient years
resulting in 8.3 crises per 100 patient years [22].
AC requires immediate substitution of 100 mg hydrocortisone as
intravenous bolus, followed by 100–300 mg hydrocortisone as a
continuous infusion over 24 h [21]
[23]. Furthermore,
adequate fluid replacement with physiological saline solution (NaCl 0.9%
intravenously, initially 1L/h) under continuous cardiac monitoring is
necessary. If the reason for the patient’s impaired condition is AI,
improvement in response to glucocorticoids is usually seen within 12 h.
Precipitating factors of AC such as infections should be treated in addition
(e.g. antibiotics, low-dose heparin treatment, prophylaxis of stress ulcer)
[23]. Depending on the clinical
condition of the patient, the steroid dosage may be reduced the following day
and then tapered to the patient’s individual daily dose.
It is worrisome that even in well-treated AI patients AC occurs. Retrospective
data demonstrate that about half of the patients with chronic AI have already
experienced at least one AC since diagnosis [7]
[17]
[18]. Hahner et al. showed in the
prospective study that patients with a previous AC were at higher risk of crisis
(odds ratio 2.85) [22]. Of note, most
of these patients with history of AC were more proactive in adaptation of their
glucocorticoid replacement dose, e.g. in case of fever, indicating good
educational status but increased vulnerability towards AC [22]. For several patients of this
study, the first crisis was lethal. Additional risk factors identified were
female sex, primary AI, diabetes insipidus and concomitant non-endocrine disease
[7]
[17]
[18].
Current concepts of glucocorticoid replacement doses and adjustments
The challenge of management is to tailor the glucocorticoid replacement therapy
to the needs of each patient [24]:
the daily maintenance dose, the daily dose/ exposure of cortisol
required to mimic normal physiology, and the need for extra cortisol during an
intercurrent illness or non-illness–related events, such as exercise, in
order to prevent AC.
Hydrocortisone is the most commonly used glucocorticoid for AI therapy [25] and is administered between twice
and four times daily with the highest dose in the morning [26]. The physiological daily cortisol
production rate is 5–10 mg/m2 body surface
[27], suggesting daily doses
between 10 and 25 mg hydrocortisone in AI patients. Doses should be
customized on an individual basis, may be guided by weight-related regimens
[28] and concomitant medications
need to be considered [24]. This
individual tailoring is expressed by the recently presented 25 different
regimens used to deliver a daily hydrocortisone dose of 20 mg in AI
patients [25].
However, current glucocorticoid replacement therapy in patients with AI does not
mimic the exact physiological rhythm, e.g. the ultra-circadian rhythm. In
addition, over-replacement of hydrocortisone may lead to increased mortality and
increased cardiovascular morbidity [9]
[10], whereas
under-replacement can result in significant impairment of quality of life and
could lead to life-threatening AC if the patient develops an intercurrent
illness.
The physiological cortisol production in healthy individuals is highly variable
during the day and further influenced by many factors that activate stress
responses like physical activity, pain, infections, psychological stress, low
blood glucose etc. Therefore, it is crucial in our current understanding that we
use the lowest possible daily hydrocortisone dose to prevent cardiovascular and
metabolic comorbidities. However, it is necessary to teach and instruct the
patient to adapt doses in the case of an intercurrent illness or
non-illness-related events.
In case of defined strong and prolonged physical activity (e.g. intensive fitness
training or running for several hours) an additional hydrocortisone dose of
5–10 mg is recommended. In contrast, short physical activity
does not seem to require additional doses [29]
[30]. An additional
dose of hydrocortisone might also be considered in situations of severe and
prolonged psychological stress (e.g. death of a relative, acute depression) as
such conditions have also been reported to cause AC [22]. Ideally the additional dose
should be given well before – not at the time of – the expected
stress, however this is often difficult to foresee. It is important to timely
reduce the hydrocortisone dose back to the standard dose to avoid
over-replacement. Short lasting stressors usually do not routinely require dose
adaptation. In case of minor physical stress (infectious diseases with fever,
stress, surgery under local anesthesia) or major and prolonged psychological
stress, the daily hydrocortisone replacement dose should be doubled or tripled
to approximately 40–50 mg/day [31]. Under conditions of medium or
major physical stress (trauma, surgery with general anesthesia, delivery) and in
case of diarrhea/vomiting hydrocortisone needs to be substituted
intravenously (100–250 mg/24h) [31].
All patients with AI should receive a national steroid emergency card [32], which gives information on the
underlying cause, the current replacement regime, and the responsible
endocrinologist. They should also be provided with the newly created European
emergency card [33]
[34]. In addition, some patients wear a
Medic-Alert bracelet, necklace, or anklet providing an emergency phone number to
access the patient’s clinical details.
Every AI patient should be equipped with a glucocorticoid emergency kit
containing additional hydrocortisone tablets, rectal prednisolone suppositories
(which are easily administered and useful for travels), and a hydrocortisone
emergency kit (e.g. ampoule with 100 mg
hydrocortisone-21-hydrogensuccinate for intramuscular injection) including
syringes. The prerequisite is that patients (together with relatives) are
educated in self-administration of hydrocortisone as intramuscular injection in
emergency situations.
Current shortcomings
National and the European emergency card are not distributed well
enough.In a survey of patients with AI, 94% of respondents carried a
national emergency card [18], but the
card was not homogenous. 73% of the German endocrine centers hand out
the emergency card of the German patients’ self-help network
(Netzwerk für Hypophysen- und Nebennierenerkrankungen e.V.),
whereas 16% use emergency cards distributed from 4 different
pharmaceutical companies, and 6% use self-made emergency cards [35]. These different national cards
reduce the recognition value among emergency personnel and might lead to
disbelief and ignorance among emergency staff regarding the patient’s
underlying illness. Furthermore, the National German Audit of Diagnosis,
Treatment, and Teaching in Secondary Adrenal Insufficiency of 50 endocrine
centers revealed that only 51% of the centers distribute the German
version of the European emergency card [33]
[34] to their patients,
whereas 49% did not [35].
Medical personnel are frequently not reacting as recommended in emergency
situations with AI patients.A retrospective study comparing reported
time intervals with time targets recommended by an European expert panel
revealed a delay of glucocorticoid administration by medical professionals in
46% of cases [36]. Only
54% of the patients received glucocorticoids parenterally within
30 min (with a range of 2-2400 min) after presentation of the
emergency card to the medical professional [36]. The European expert panel considered 30 min as time
limit for “card-injection-time” in case of an AC within the same
trial [36]. A recent prospective
evaluation of emergency management showed a large variability in emergency
measures: the median time from showing the emergency card to a medical
professional to parenteral glucocorticoid administration by a medical
professional (card-injection-time) was 60 min (5–360). Only
45% of the patients received glucocorticoids by a physician within
30 min [37]. One reason for
this shortcoming might be insufficient knowledge of physicians of AI. Only less
than 10% of interviewed physicians identified all situations requiring
glucocorticoid adjustment correctly [38]
[39]. Another reason
might be the low recognition value of different emergency cards handed out to
patients.
Patients are not equipped for emergency situations.Only 30% of AI
patients possessed a glucocorticoid emergency kit. 10% reported that
they had never increased their glucocorticoid dose [18]. The German national audit
regarding SAI patients revealed that only 61% of the centers prescribe
additional hydrocortisone tablets, only 59% prescribed
prednisone/ prednisolone suppositories, 65% a 100 mg
hydrocortisone ampoule, 2% a 50 mg prednisolone ampoule,
4% hydrocortisone suppositories, and 5% betamethasone liquid
[35].
Patients are not educated well enough for emergency situations.Only a few
patients were able to or knew how to self-inject, and most of them relied on
medical personnel for emergency glucocorticoid replacement treatment [17]. In the German national audit
84% of the centers answered that they perform patient education, which
was mostly done on an unstructured basis and took place during the short
consulting time (average appointment time 5–15 min) [35]. Furthermore, in 47.8% of
the centers patient education is done by the doctor, in 28.8% of the
centers by the doctor’s assistant, in 14.5% by a trained
endocrine nurse, in 7.4% of the centers by a nurse or study nurse, and
in 2.5% of centers by a diabetes nurse. Relatives are involved in
patient education only in 52% of the centers [35]. Recent data from a prospective
study showed that patients who performed a self-injection had an improved
outcome: after initial parenteral (intramuscular or subcutaneous) glucocorticoid
administration by patients or their relatives, significantly more patients were
treated on an outpatient basis (62%) compared to patients who did not
self-inject (27%), (p=0.008) [37]. Two surveys from 2013 and
2017/18 in British patients revealed that within a 5-year interval more
patients performed self-injection for treatment of emergency situations
(16.7% versus 24%) [40].
The content of patient education is very heterogenous among centers.Among
German endocrine centers there is a broad agreement on advices given to patients
regarding behavior in conditions, such as diarrhea, fever of 38.5°C and
light fever (flu) [35]. However,
recommendations and patient education varied considerably regarding situations
involving psychological stress, 60 min sport activity, common cold
(without fever), coughing (without fever), or dental treatment [35].
Patients have concerns and fears regarding their illness and their
therapy.Nonadherence has been recognized as a significant challenge by
the World Health Organization suggesting that only 50% of patients with
chronic conditions take their medications as recommended. In AI, 23% of
patients report dissatisfaction with treatment, 38% find multiple daily
dosing problematic, over 50% perceive that glucocorticoids interfere
with life aspects such as work, travel or sex life, and many missed tablets or
took them before sleep which resulted in fatigue or insomnia [41]. Recent data report poor adherence
of AI patients [42] and reveal many
concerns regarding patients’ glucocorticoid replacement therapy and
possible side events [43]. A study
analyzing patient’s diary data revealed that the perception of
discomfort does not always seem to result in a glucocorticoid dose increase in
AI patients, especially in situations indicating GI infection. On the other
hand, possible over-dosing was seen in some patients [44].
Aims of Patient Education
All patients with AI must receive a structured crisis prevention education together
with their partners or relatives and this should be given at the time of first
diagnosis [31]. In addition, during each
follow-up visit (ideally twice a year) the patient should be trained in recognizing
typical stressful situations (fever, infection, stress, surgery or trauma) and
symptoms of acute AI, and instructed on glucocorticoid dose adjustment in these
situations. Therefore, patient education is currently the most important measure for
prevention of AC [45]. It should be
stressed that patient education is part of the endocrinologist’s therapeutic
responsibility.
We believe that it is necessary to implement a structured education and treatment
program for patients with AI. Therefore, we recently started to develop and
implement a structured patient education program in Germany [46]. This was initiated by nine tertiary
endocrine centers across Germany and the section “Nebenniere, Steroide und
Hypertonie” of the German Endocrine Society (DGE) by the end of 2014.
The aim is:
-
to provide a homogeneous and structured patient education across Germany
-
to impart knowledge to AI patients about their condition
-
to encourage and enable patients to adjust their hydrocortisone medication in
special situations, thereby regaining independence and improving their
radius of action
-
to empower patients to take care of themselves
-
to provide a platform for exchange of experience between participating
patients
-
to train self-, respectively partner-injection of parenteral hydrocortisone
in case of emergency
-
to prevent adrenal crises.
Since then, on a yearly basis the section “Nebenniere, Steroide und
Hypertonie” offers a 6–8 h certification course called
“Structured patient education for patients with AI” to interested
endocrine centers. For each center it is obligatory that an endocrinologist and an
endocrine nurse/ endocrine assistant take part as tandem. The program
includes the following topics: presentation of the project, data regarding quality
of disease management in patients with AI (background and why we need a structured
patient education program), results of the evaluation of the German structured
patient education program, presentation of the patient education program (structure,
content, messages, learning points, hand-on exercise: emergency injection) and an
interactive group work. After successful participation in the certification course,
the endocrine centers are qualified for the use of the patient education program.
Standardized training materials (and the patient education program) are available
to
all qualified teaching teams via an internet-based platform (cloud). Starting from
8
centers in 2014, this patient education program has been provided to 77 endocrine
centers by the end of 2018 with 186 medical personnel to educate AI patients in a
standardized manner ([Fig. 1]).
Fig. 1 Endocrine centers in Germany and neighboring countries who were
instructed with the structured patient education program of the section
“Nebenniere, Steroide und Hypertonie” of the German
Endocrine Society (DGE) by end of 2018, and who offer a standardized patient
education program on a regular (black) or an irregular (light grey) basis
(with friendly permission of Smadar Pahl, Oldenburg, Germany).
Results of Patient Education
A structured patient education program has been implemented in the Netherlands and
proven to be beneficial especially regarding improved patients’ knowledge
about their disease, dose adaptation in situations of intercurrent illness and
emergency situations [47].
Since the introduction of the German national structured and certified patient
education program in November 2014 the number of centers employing this structured
program has been steadily growing in Germany ([Fig. 1]). By the end of 2018 1365 group education sessions for 2907 AI
patients were given in addition to 770 individual education sessions.
First evaluations of the program revealed a significant and lasting gain in knowledge
on AI in general and on the prevention and management of AC [48]. Patients furthermore felt encouraged
to manage emergency situations [48].
Whereas only 84% of participants were equipped with an emergency card and
49% possessed an emergency kit before participation in the program, all
participants received both card and prescription of glucocorticoids for emergency
use. Detailed results on the evaluation of the program will be published elsewhere.
In a recent prospective analysis of the emergency management in 150 German patients
with AI, 32% reported that they had performed self-injection and further
15% of patients reported glucocorticoid injection by a family member [37]. Of these study participants,
71% had participated in the standardized patient education program. In
contrast, only 6% of respondents from the 2003 survey of the British
Addison’s disease self-helping group reported management of adrenal
emergency by glucocorticoid self-injection [40]. First preliminary evaluations of the patient education program among
patients with secondary AI in our center in Berlin (23 women, 21 men; median age
60.5 yrs, range 18–83 yrs; median duration of disease 5 yrs, range
0–40 yrs) showed that the patient’s knowledge significantly
increased after patient education and remained reasonably stable after 6–9
months. Furthermore, patients rated their general information status on AI as
significantly improved (p<0.001) after the standardized education ([Fig. 2]). In addition, more patients
(52.3% vs. 72.7%, p=0.154) stated that they would dare to
perform a self-injection after participation in the standardized education compared
to before education ([Fig. 3]).
Fig. 2 Patients’ self-assessment of the information status on
AI (n=44) before, after, and 6-9 months after standardised patient
education. The scale ranges from “very good” to
“very bad”. Chi-Square test was performed to compare rating
“very well”+”well” versus rating
“satisfactory”+”badly”+”very
badly”.
Fig. 3 Percentage of patients with secondary AI (n=44) who
would dare to perform a self-injection before, directly after, and 6-9
months after patient education. Chi-Square test was performed to compare
percentage of self-injection.
Another recent study investigated the effect of providing information regarding AI,
AC and its management to 77 parents of children with congenital adrenal hyperplasia
(CAH) [49]. They described a significant,
positive relationship between detailed instruction to parents on AC management and
perceived management ability [49]. This
resulted in the observation that the stronger the perceived management ability was,
the less impact the children’s diagnosis of CAH had on the family [49].
Recently it was shown that longitudinal scores of the disease specific-QoL
questionnaire AddiQoL and self-reporting of pre-crises via patient diaries are
additional clinical tools to identify higher risks for critical events [50]. We think that those methods for
self-evaluation towards early detection of clinical symptoms, also including glucose
profiles on CGM devices in diabetic patients with AI, will enable patients to adjust
their glucocorticoid medication in special situations and thereby to regain
independence and to take care of themselves.
However, the established educational programs are suited to the well-informed,
cooperative and compliant patient. Several patients experience social decline during
the disorder, are lost to follow-up and not reached by caregivers. This needs to be
addressed in future programs. Furthermore, due to the fact that iatrogenic AI is
often overlooked, patients on immuno-suppressive, or -modulatory glucocorticoid
dosages may suffer morbidity and even die prematurely [8]. Such patients are not yet routinely
identified and included in educational programs.
In summary, the current literature showed a significant gain of knowledge on AI in
general, an increased understanding for dose adaptation in situations of
intercurrent illness, and a higher self-confidence to perform a self-injection of
hydrocortisone after participation in a patient education program.
AI Management and education during COVID-19
Because lockdown and quarantine situations might occur, it is important that AI
patients have enough supply of glucocorticoid tablets and their emergency set
updated. The educated AI patient doubles or triples the daily hydrocortisone dose
to
approximately 40–50 mg/day in case of infectious diseases with
fever. In the case of illness immediate release, regular oral hydrocortisone should
be preferred over modified release hydrocortisone preparations [51]. As it relates to COVID-19, any
patient with a dry continuous cough or mild fever should immediately double their
daily oral glucocorticoid dose and continue on this regimen until the fever or the
cough has subsided [52]
[53]. Other authors suggest that an acute
COVID-19 infection is associated with significant and persistent acute inflammation
and often continuous high fever, which probably requires a more evenly spaced
glucocorticoid cover throughout day and night (20 mg oral hydrocortisone every
6 h) [51]. An Italian article
suggests in the case of suspected pneumonia (fever >38°C and signs
of lower respiratory tract symptoms (persistent cough, respiratory rate >30
breaths/min, severe respiratory distress, SpO2 93% on
room air, hypotension) a hospitalization should be advised and hydrocortisone dose
increased to 100 mg/day [53]. Contrary to the general population, the threshold for
hospitalization should be low for worsening symptoms in AI patients, considering
their risk for an AC [53].
Deteriorating patients and those who experience vomiting or diarrhea should seek
urgent medical care, use their emergency set (100 mg hydrocortisone i.m.) and be
treated with parenteral physiological stress doses of hydrocortisone (50–100
mg intravenously t.i.d.) in the clinic [52].
The standardized patient education program cannot be organized as a personal meeting
during a complete lockdown situation experienced recently in several countries due
to the COVID-19 pandemic. Under such circumstances the patient education program
should be transferred to an interactive online meeting using web-conference and
electronic meeting systems (e.g. ZOOM, Skype). However, the personal and direct
learning of the hydrocortisone emergency self-injection is not possible. Under a
partial lockdown situation which allows small group meetings (3–5 persons),
the patient education program could be organized with precaution measures such as
obligatory wearing of face masks of all participants, 2 m distance between
the participants and with a good room ventilation. In addition, the session time
should be restricted to 45 min with inclusion of the most important part of
the education program: learning of the emergency hydrocortisone self-injection. The
remaining 60–90 min teaching could be transferred to an interactive
online meeting as mentioned above. The patient education program should be amended
with guidance regarding stringent social distancing rules [51], use and handling of face masks,
correct handwashing etc, because only these behavioral measures can prevent a
primary SARS-COV2 exposure. Recently, UK/Swiss sociologists provided a
mathematical model to illustrate, how strategies for reducing and selecting social
contacts (limiting interaction to a few repeated contacts akin to forming social
bubbles; seeking similarity across contacts; and strengthening communities via
triadic strategies) will be efficient and can avoid complete isolation [54].
Furthermore, online platforms providing qualified AI patient information, such as
Addison’s self help group
(https://www.addisonsdisease.org.uk) and Adrenal.eu
(https://adrenals.eu) should be integrated into the patient
education program.
