Key words
desmopressin - central diabetes insipidus - intranasal - oral - arginine vasopressin
- adults
Introduction
Central diabetes insipidus (cDI) is a rare disorder characterized by hypotonic
polyuria due to a deficiency in the secretion of antidiuretic hormone from the
pituitary gland. The various etiologies of DI include congenital and acquired causes
[1]
[2]. Most cases of cDI are acquired and may be due to neoplasm, infection,
head trauma, hypophysitis, or surgery affecting the pituitary gland with the
majority being due to neurosurgery, which may lead to both partial cDI and complete
cDI [3]
[4].
The congenital etiologies include genetic etiologies, which are characterized by a
deficiency in the secretion of the antidiuretic hormone due to pathogenic variants
in the arginine vasopressin (AVP) gene, with at least 83 known variants [3]. There are at least five different forms of
hereditary cDI. The most common is inherited in an autosomal dominant mode, caused
by the mutant precursor to misfold, accumulate and in the end destroy the
magnocellular neurons, which later leads to inhibited expression of the normal
allele. At the beginning of this form of DI, the deficiency of AVP is partial and
the symptoms typically begin to appear from the age of 6 months to 6 years and
usually progress to a severe if not complete lack of AVP [5].
The diagnosis of DI is based on a water deprivation test and once the patient has
been diagnosed with DI, they should be treated with a vasopressin analogue –
desmopressin [6]. Desmopressin can be
administered in oral, sublingual, and intranasal forms. Bioavailability and onset
of
action are higher and faster for the intranasal form compared to the oral
administration, though the effectiveness of the intranasal administration may be
reduced if there is nasal mucosa inflammation [5]. An earlier study found that children with a higher body mass index
(BMI) needed higher doses of desmopressin [1].
In addition, associations between dose, age, and weight have previously been
reported [7]. Hyponatremia is the major
complication when treated with desmopressin [6] and earlier studies have found a higher risk of hyponatremia in
patients using intranasal administration compared to oral administration [8]
[9].
Hence, treatment with vasopressin analogues often requires close monitoring to
ensure the most optimal desmopressin dose in order to obtain the best effect and no
or little side effects [8]. Chronic
hyponatremia affects the ability to walk and increases the risk of falls, fractures,
seizures, and mortality [10]
[11] emphasizing the need for careful monitoring
of sodium levels in patients with DI.
The main objective of this study was to compare the desmopressin dose requirements
in
DI patients with a congenital etiology with patients having acquired DI. The second
objective was to assess the association between BMI and desmopressin dose
requirements and the risk of hyponatremia in patients using different modes of
desmopressin administration.
Hypothesis
We hypothesized that patients with congenital DI have higher daily dose
requirements of desmopressin compared with patients having acquired DI. Also,
that the daily desmopressin dose requirement was positively associated with BMI,
and that patients treated with intranasal desmopressin would have lower sodium
levels compared to patients receiving oral desmopressin.
Patients and Methods
Study design
This study was a retrospective study including all patients with cDI and treated
with desmopressin attending Department of Medical Endocrinology and Metabolism
at Rigshospitalet, Copenhagen, Denmark during 2022. Diagnosis was based on
clinical assessment or by water deprivation test. Patients with nephrogenic DI
or gestational DI were excluded. Patient files were retrospectively assessed,
and the following data were registered: sex, current age, disease duration,
weight (kg), BMI, etiology of DI, desmopressin doses (μg), desmopressin
administration, adjusted dose at last consultation, concurrent pituitary
deficiencies, the lowest Na-concentration measured in the past 12 months
(mmol/l) and hospitalizations due to hyponatremia within the last two
years. In Denmark, a sodium concentration lower than 136 mmol/l
is used as the threshold value for hyponatremia. Regarding controls of sodium
concentration, there is no specific test interval, while our Danish guidelines
suggest every 6–12 months in patients with DI who are in stable
treatment.
Primary outcome
The etiology of DI was classified as either congenital or acquired. Congenital
etiologies included genetic mutations and structural brain abnormalities [1]. Acquired etiologies included pituitary
tumors, craniopharyngioma, other CNS tumors, idiopathic etiologies, and
hypophysitis [12]. Hypophysitis included
primary and secondary hypophysitis (Langerhans cell histiocytosis,
sarcoidosis, and Wegener’s granulomatosis) [13]. Daily desmopressin doses between the
different etiologies and patient characteristics were compared.
For calculation of the daily dose requirements, we converted the nasal and
sublingual doses to the equivalent oral doses. Previous studies have found a
bioavailability of 10–20 times higher with the nasal administration than
with the oral form [5]
[9]
[14]
[15]
[16]. Based on previous practice, we decided
to multiply the dose with 20 when converting nasal dose to oral dose, and
multiply with 1.67 when converting sublingual dose to oral dose [3]
[7]. The “desmopressin dose requirement” was calculated as
the sum of all desmopressin taken during one day after converting it to the
equivalent oral doses.
Secondary outcomes
The association between BMI and daily dose requirements of desmopressin were
assessed by linear regression with desmopressin dose requirement as the
dependent variable and BMI as the independent variable. The association between
type of medication, that is, intranasal versus oral tablets, and risk of
hyponatremia was conducted by comparing the number of patients who had
experienced hyponatremia at least once in the past 12 months. Mild hyponatremia
was defined as a sodium concentration<136 mmol/l, and
moderate hyponatremia was defined as a sodium
concentration<131 mmol/l as in an earlier study by
Garrahy et al. (2019) [10].
Post-hoc analysis
In addition to the pre-planned analysis, the association between desmopressin
dose and patient characteristics were assessed by comparing daily desmopressin
dose requirement and sex, current age, years with diagnosis, weight (kg), other
pituitary deficiencies, adjusted dose at last consultation, and concurrent
pituitary deficiencies. Moreover, daily desmopressin doses between patients with
DI due to pituitary tumors and craniopharyngiomas were compared.
Statistics
All continuous variables were reported in median (Mdn) and interquartile range
(IQR) as the 25th and 75th percentile while categorical variables were reported
in percentages. Continuous variables were compared using Mann–Whitney U
non-parametric test whereas categorical variables were compared using the
χ2-test. When testing for associations between daily dose
requirement and patient characteristics we used linear regression. A
p-value≤0.05 was considered statistically significant, and for inclusion
in the multivariate analysis, we included all variables with univariate
association of p<0.2 in order to avoid overfitting of the final model.
In case of a strong correlation between independent variables, for example,
weight and BMI, the variable with the strongest association assessed by the
standardized beta value was included in the multivariate analysis. Data were
analyzed using the statistical software SPSS, version 28.0 (IBM Corp).
Results
Patient characteristics
A total of 225 patients with suspected DI were identified and three patients were
excluded due to either gestational DI or because DI was no longer suspected,
thus 222 patients were included in the current study. The majority of patients
were female 130/222 (58.6%) with a median age of 53 (IQR: 35 to
63) years and a median disease duration with DI of 11 (IQR: 5 to 19) years. The
different etiologies included patients with acquired etiologies
(n=215/222; 96.8%) and congenital etiologies
(n=7/222; 3.2%), of which five were genetic and two were
structural brain abnormalities. The most common acquired causes were pituitary
tumors (n=84/222; 37.8%), craniopharyngioma
(n=57/222; 25.7%), other CNS-tumors
(n=21/222; 9.5%), and hypophysitis
(n=19/222; 8.7%). Diabetes insipidus were confirmed with
a water deprivation test in 23/222 (10.4%). The patients were
treated with different forms of administration; 134/222 (60.4%)
received oral tablets, 41/222 (18.5%) nasal spray and
32/222 (14.1%) sublingual melt tablets. The remaining
15/222 (6.8%) were treated with a combination of at least two
forms of administration. The patient characteristics are summarized in [Table 1].
Table 1 Patient characteristics.
|
Characteristics
|
Total (n=222)
|
|
Female, n (%)
|
130/222 (58.6)
|
|
Age, median (IQR)
|
53 (35 to 63)
|
|
Disease duration, median (IQR)
|
11 (5 to 19)
|
|
BMI, median (IQR)
|
27.5 (24.4 to 32.0)
|
|
DI confirmed with water deprivation test, n
(%)
|
23 (10.4)
|
|
Etiologies, n (%)
|
|
|
Pituitary tumors
|
84 (37.8)
|
|
Craniopharyngioma
|
57 (25.7)
|
|
Other CNS tumors
|
21 (9.5)
|
|
Hypophysitis
|
19 (8.6)
|
|
Congenital
|
7 (3.2)
|
|
Idiopathic
|
10 (4.5)
|
|
Other
|
24 (10.8)
|
|
Form of desmopressin administration, n (%)
|
|
|
Oral
|
134 (60.4)
|
|
Intranasal
|
41 (18.5)
|
|
Sublingual
|
32 (14.4)
|
|
More than one form of administration
|
15 (6.8)
|
|
Daily desmopressin dose (microgram/Day)
|
|
|
Daily desmopressin dose, median (IQR)
|
200 (100 to 400)
|
|
Oral tablets, median (IQR)
|
200 (100 to 300)
|
|
Nasal spray, median (IQR)
|
20 (10 to 30)
|
|
Sublingual melt tablets, median (IQR)
|
135 (75 to 240)
|
|
Experiencing hyponatremia in the past 12 months
|
|
|
All cases with sodium
level<136 mmol/l, n (%)
|
66/215 (30.7)
|
|
Severe hyponatremia, n (%)
|
20/215 (9.3)
|
|
Other pituitary hormone deficiencies, n
(%)
|
198 (89.2)
|
|
Thyroid deficiency
|
194 (87.4)
|
|
Adrenal insufficiency
|
157 (70.7)
|
|
Gonadotropin deficiency
|
148 (66.7)
|
|
Growth hormone deficiency
|
134 (60.4)
|
|
Time of day when desmopressin is taken, n
(%)
|
|
|
Morning
|
155/213 (72.8)
|
|
Noon
|
83/213 (39.0)
|
|
Evening
|
112/213 (52.6)
|
|
Night
|
115/213 (54.0)
|
Desmopressin dose in congenital versus acquired DI
The median daily dose requirement in the acquired group was 200 mcg (IQR
100 to 400) versus 600 μg (IQR 200 to 900) in patients with
congenital DI (p=0.005), as illustrated in [Fig. 1]. Patients with acquired DI were
older (p=0.0005), had shorter disease duration (p=0.04), and
were more likely to have other pituitary deficiencies
(n=196/215; 91.2%) compared to patients with congenital
DI (n=2/7; 28.6%), (p=0.0005). Patients with
acquired DI were more likely to use oral administration (p=0.0005) while
patients with congenital DI were more likely to use sublingual (p=0.03)
or more than one type of administration (p=0.02), as shown in [Table 2].
Fig. 1 Daily desmopressin dose requirements in patients with
acquired (n=215) or congenital (n=7) diabetes insipidus
(DI) (p=0.005).
Table 2 Comparison of characteristics of acquired and
congenital DI.
|
Acquired
|
Congenital
|
p-Value
|
|
n
|
215
|
7
|
|
|
Female (%)
|
125 (58.1)
|
5 (71.4)
|
0.5
|
|
Age, median (IQR)
|
54 (36 to 63)
|
27 (24 to 34)
|
0.0005
|
|
Disease duration, median (IQR)
|
11 (5 to 18)
|
20 (16 to 25)
|
0.04
|
|
BMI, median (IQR)
|
27.5 (25 to 32)
|
26.6 (20 to 37)
|
0.6
|
|
Weight, median (IQR)
|
85 (73 to 97)
|
79 (58 to 112)
|
0.6
|
|
Daily dose requirement (μg), median (IQR)
|
200 (100 to 400)
|
600 (200 to 900)
|
0.005
|
|
Na-concentration, median (IQR)
|
138 (135 to 139)
|
136 (132 to 137)
|
0.3
|
|
Hyponatremia,<136 mmol/l, n
(%)
|
20/211 (9.5)
|
2/4 (50)
|
0.4
|
|
Severe hyponatremia,<131 n (%)
|
64/211 (30.3)
|
0 (0)
|
0.5
|
|
Adjusted dose at last consultation, n (%)
|
14 (6.5)
|
0 (0)
|
0.5
|
|
Other pituitary deficiencies, n (%)
|
196 (91.2)
|
2 (28.6)
|
0.0005
|
|
Thyroid deficiency, n (%)
|
192 (89.3)
|
2 (28.6)
|
0.0005
|
|
Gonadotropin deficiency, n (%)
|
146 (67.9)
|
2 (28.6)
|
0.03
|
|
Adrenal insufficiency, n (%)
|
155 (72.1)
|
2 (28.6)
|
0.01
|
|
Growth hormone deficiency, n (%)
|
132 (61.4)
|
2 (28.6)
|
0.08
|
|
Oral administration, n (%)
|
134 (62.3)
|
0.(0)
|
0.0005
|
|
Nasal administration, n (%)
|
39 (18.1)
|
2 (28.6)
|
0.5
|
|
Sublingual administration, n (%)
|
29 (13.5)
|
3 (42.9)
|
0.03
|
|
More than one form of administration, n (%)
|
13 (6.0)
|
2 (28.6)
|
0.02
|
The “Daily dose requirement” was calculated as the sum of
all desmopressin taken during 24 hours after converting it to
the equivalent oral doses. Na-concentration denotes the lowest sodium
level measured in the past 12 months.
Desmopressin dose and BMI
There was no association between BMI and desmopressin dose requirement
(p=0.6) when assessing the whole population. However, as shown in [Table 3], body weight was positively
associated with dose requirements in multivariate analysis (p=0.048).
Post-hoc analysis restricted to patients who used oral desmopressin supported
the finding of a positive association between dose and weight (p=0.003),
while this was not confirmed in patients using nasal spray or sublingual melt
tablets (all p-values>0.5). As shown in [Table 4], the association between weight
and oral desmopressin was further explored in a multivariate analysis finding a
borderline significant association between BMI and oral dose requirement
(p=0.05) and a stronger association between weight and oral dose
requirement of desmopressin.
Table 3 The association between daily desmopressin dose
and patient characteristics in linear regression
analysis.
|
Independent variable
|
B-value (CI)
|
p-Value
|
Multivariate
|
p-Value
|
|
Female
|
–47.1 (–111.2 to 17.1)
|
0.15
|
–49.1 (–114.0 to 15.8)
|
0.1
|
|
Age
|
–2.6 (–4.3 to –0.9)
|
0.003
|
–3.0 (–4.7 to –1.3)
|
0.0005
|
|
Disease duration
|
6.4 (4.1 to 8.7)
|
0.0005
|
6.9 (4.6 to 9.2)
|
0.0005
|
|
Age at the diagnosis
|
–4.4 (–5.8 to –3.0)
|
0.0005
|
|
|
|
BMI
|
2.0 (CI: –3.1 to 7.0)
|
0.6
|
|
|
|
Weight (kg)
|
1.3 (0.0 to 2.5)
|
0.048
|
1.7 (0.2 to 3.3)
|
0.03
|
|
Na-concentration (mmol/l)
|
–3.0 (–10.1 to 4.1)
|
0.4
|
|
|
|
Adrenal deficiency
|
–65.9 (–135.1 to 3.3)
|
0.06
|
–33.8 (–111.7 to 44.2)
|
0.4
|
|
Thyroid deficiency
|
–99.3 (–194.0 to –4.6)
|
0.04
|
–68.6 (–177.8 to 40.5)
|
0.2
|
|
Gonad-axis replacement
|
–9.0 (–76.3 to 58.3)
|
0.8
|
|
|
|
Growth hormone deficiency
|
18.2 (–46.6 to 83.1)
|
0.6
|
|
|
A multivariate model including age at diagnosis rather than years living
with DI produced similar results.
Table 4 The association between patient characteristics
and dose requirements using linear regression model in patients
treated with oral tablets (n=134).
|
Independent variable
|
B-value (CI)
|
p-Value
|
Multivariate
|
p-Value
|
|
Female
|
–39.5 (–104.1 to 25.0)
|
0.2
|
|
|
|
Age
|
–1.9 (–3.8 to –0.1)
|
0.04
|
–2.3 (–4.1 to –0.6)
|
0.01
|
|
Disease duration
|
5.1 (2.7 to 7.4)
|
0.0005
|
5.8 (3.4 to 8.1)
|
0.0005
|
|
Age at the diagnosis
|
–3.8 (–5.4 to –2.2)
|
0.0005
|
|
|
|
BMI
|
5.1 (–0.0 to 10.3)
|
0.05
|
|
|
|
Weight (kg)
|
2.4 (0.8 to 4.0)
|
0.003
|
2.5 (1.1 to 4.0)
|
0.0005
|
|
Na-concentration (mmol/l)
|
3.8 (–3.1 to 10.6)
|
0.3
|
|
|
|
Adrenal deficiency
|
18.5 (–53.7 to 90.8)
|
0.6
|
|
|
|
Thyroid deficiency
|
–50.8 (–171.3 to 69.7)
|
0.4
|
|
|
|
Gonad-axis replacement
|
39.0 (–29.1 to 107.1)
|
0.3
|
|
|
|
Growth hormone deficiency
|
87.6 (24.8 to 150.3)
|
0.007
|
57.5 (–2.5 to 117.6)
|
0.06
|
The dependent variable is oral desmopressin dose
(μg/day); Na-concentration denotes the lowest sodium
level measured in the past 12 months; Including ‘BMI’
rather than ‘Weight’ did not markedly change the
multivariate analysis.
Administration form and risk of hyponatremia
During the last two years 5/222 (3.7%) patients were hospitalized
due to hyponatremia, all of whom received desmopressin as oral tablets. During
the last 12 months, 66/215 (30.7%) had sodium levels
136 mmol/l including 20/215 (9.3%) with severe
hyponatremia. Sodium levels<136 mmol/l occurred in
38/131 (29%) of patients using oral tablets compared to
12/40 (30%) inpatients using nasal spray (p=0.9), as
shown in [Table 5]. Nor was there any
difference between the proportion of patients with severe hyponatremia
(Na<131 mmol/L) in patients using oral tablets
n=12/131 (9.2%) compared to patients using nasal spray
n=4/40 (10%) (p=0.9). Among the group treated
with sublingual melt tablets 11/32 (22.4%) patients experienced
sodium levels<136 mmol/l, which was no different from
either oral tablets (p=0.5) or nasal spray (p=0.6). Severe
hyponatremia was experienced in 2/32 (6.5%) patients treated
with sublingual tablets, which did not defer from oral tablets (p=0.6)
or nasal spray (p=0.6), as shown in Supplementary
Table 4 S and Supplementary
Table 5 S.
Table 5 Characteristics of patients treated with oral
tablets and nasal spray.
|
Oral tablets
|
Nasal spray
|
p-Value
|
|
n
|
134
|
41
|
|
|
Female, n (%)
|
81 (60.4)
|
23 (56.1)
|
0.6
|
|
Age, median (IQR)
|
57 (42 to 67)
|
45 (30 to 55)
|
0.0001
|
|
Disease duration, median (IQR)
|
8 (4 to 16)
|
16 (12 to 27)
|
0.0001
|
|
BMI, median (IQR)
|
28 (25 to 32)
|
27 (25 to 31)
|
0.4
|
|
Weight, median (IQR)
|
85 (74 to 97)
|
85 (67 to 101)
|
0.7
|
|
Na-concentration, median (IQR)
|
138 (135 to 140)
|
138 (135 to 140)
|
0.8
|
|
Hyponatremia,<136, n (%)
|
38/131 (29.0)
|
12/40 (30.0)
|
0.9
|
|
Severe hyponatremia,<131 n (%)
|
12/131 (9.2)
|
4/40 (10.0)
|
0.9
|
|
Hospitalizations due to hyponatremia, n (%)
|
5 (3.7)
|
0 (0)
|
0.2
|
|
Adjusted dose at last consultation, n (%)
|
9 (6.7)
|
2 (4.9)
|
0.7
|
|
Thyroid deficiency, n (%)
|
124 (92.5)
|
35 (85.4)
|
0.2
|
|
Gonadotropin deficiency, n (%)
|
92 (68.7)
|
28 (68.3)
|
0.97
|
|
Adrenal insufficiency, n (%)
|
99 (73.9)
|
29 (70.7)
|
0.7
|
|
Growth hormone deficiency, n (%)
|
79 (59)
|
30 (73.2)
|
0.1
|
|
Desmopressin morning, n (%)
|
90/127 (70.9)
|
29 (70.7)
|
0.99
|
|
Desmopressin noon, n (%)
|
45/127 (35.4)
|
15 (36.6)
|
0.9
|
|
Desmopressin evening, n (%)
|
61/127 (48.0)
|
25 (61)
|
0.2
|
|
Desmopressin night, n (%)
|
74/127 (58.3)
|
18 (43.9)
|
0.1
|
The “Daily dose requirement” was calculated as the sum of
all desmopressin taken during 24-hours after converting it to the
equivalent oral doses. Na-concentration denotes the lowest sodium level
measured in the past 12 months.
Clinical characteristics and dose requirements
As shown in [Table 3], assessment of
clinical characteristics and daily desmopressin dose requirement suggested that
short duration of disease and older age were associated with lower daily dose
requirements. Patients with craniopharyngioma were treated with higher doses
(Mdn=300 μg; IQR: 125 to 400) compared to patients with
pituitary tumors (Mdn=200 μg; IQR: 100 to 250;
p=0.0005), as illustrated in Supplementary
Fig. 1S. The patient characteristics of pituitary tumors and
craniopharyngioma are summarized in Supplementary
Table 1S. The inverse association between duration of disease, age and
daily dose requirement were maintained after excluding patients with congenital
etiology, and when restricting the analysis to patients receiving only oral
desmopressin. This was also the case for the dose comparison of
craniopharyngioma versus pituitary tumors. Patients with onset of DI at the
age≤21 years (n=66) had significantly higher daily desmopressin
dose requirements 350 (200 to 600) than those with onset age>21
(n=156) who required 200 μg (100 to 300)
(p=0.0005). The were more patients with pituitary tumors in the group
who had an onset age>21 n=74/156 (47.4%) than
the group with earlier onset n=10/66 (15.2%),
(p=0.0005) as shown in Supplementary
Table 8S.
Discussion
We found that the daily desmopressin dose requirements of patients with congenital
DI
were higher compared to patients with acquired DI. There was no association between
BMI and dose requirements, though patients with a higher weight received higher
doses. Furthermore, type of administration mode of desmopressin did not affect risk
of hyponatremia. Other predictors of high desmopressin dose requirements were
craniopharyngioma, long duration of disease and young age at the time of
diagnosis.
Desmopressin dose in congenital versus acquired DI
According to our knowledge, only one study by Almutlaq and Eugster (2021) [1] has compared desmopressin dose
requirements between congenital and acquired cDI finding that children with
acquired cDI were more likely to require larger doses of desmopressin, than
children with congenital cDI. The deficiency of AVP is typically partial, to
begin with in children who have the most common variant of genetic cDI, and the
AVP deficiency usually progresses to a severe if not complete lack of AVP later
in life [5]. Thus, patient’s age
can be a factor of great importance when comparing the dose requirement in
patients with congenital and acquired etiologies, which may explain the opposite
finding in our study. Another discrepancy between the findings of this study and
the findings of Almutlaq and Eugster (2021) [1] was that most of the congenital etiologies were structural brain
abnormalities, contrary to this study, where genetic etiologies were more
represented. In the current study, we identified several factors associated with
variation in desmopression dose requirements: current age was inversely
associated with dose requirements, while duration of DI and weight in kg was
positively associated with daily desmopressin dose requirements. However,
patients with congenital disease were younger compared to patients with acquired
disease, and the confounding effect of age does not explain the observed
findings. The two groups had similar body weight while patients with congenital
disease had lived longer with disease, which may in itself explain the observed
differences. The difference in form of administration may be due to the fact
that the patients with congenital DI had a need for desmopressin since
childhood. Children have difficulty swallowing tablets and might be more likely
to be treated with nasal or sublingual administration. These forms of
administration may have continued into adulthood and could perhaps explain the
difference in form of administration. Due to the small number of invidivuals
with congenital disease we were not able to build a satisfactory regression
model for multivariate analysis. When comparing the groups based on DI onset
before and after the age of 21, We found that patients who had onset of DI
before the age of 21 years had greater daily desmopressin dose requirements than
those who had later age of onset. This could indicate that the dose requirement
is influenced not only by the onset during childhood but also if onset occurs
later during the teenage years. Furthermore, there were more patients with
pituitary tumors in the group with late onset of DI than in the group with
earlier onset, which also could explain the difference in daily dose
requirements. In the included cohort, our hypothesis regarding higher daily
desmopressin dose requirements were confirmed, however, this observation may be
due to confounding factors and not the disease etiology itself.
Desmopressin dose and BMI
In contrast to the study by Almutlaq and Eugster (2021) [1], we did not find any association between
dose and BMI in the full sample, however restricting our analysis to patients
receiveing oral treatment did show a positive association between BMI and daily
dose requirements. We did observe a much stronger association between higher
dose requirement and higher weight, which is in agreement with other studies of
children using oral tablets by Ooi et al. (2013) [7] and Boulgourdjian et al. (1997) [17]. Oral desmopressin must be absorbed in
the digestive system before entering the bloodstream, while nasal and sublingual
formulations are absorbed directly into the bloodstream through the mucosa [18]. This difference in pharmacokinetics
may explain why an association is seen for oral administration and not for nasal
and sublingual administration forms.
Administration form and risk of hyponatremia
During the last 12 months, 30.7% had experienced hyponatremia of which
9.3% had experienced severe. However, this did not differ between
patients having nasal administration compared to oral administration. Nor did we
find a difference in risk of hyponatremia when sublingual administration was
compared to oral tablets and nasal spray. Contrary to the current finding, other
studies have found a lower risk of hyponatremia when using oral compared to
nasal administration [7]
[12]
[19]
[20]. Almost 10% had
severe hyponatremia during the past 12 months, which may suggest administration
of too high desmopressin doses or that patients sometimes regulate dosing
themselves. In comparison a similar study by Behan, Sherlock, Moyles et al.
(2015) [21] found a prevalence of mild
hyponatremia of 27% and moderate hyponatremia of 15%, which is
in comparison with the current study.
Desmopressin dose in pituitary tumors versus craniopharyngioma
The patients with craniopharyngioma received higher doses than patients with
pituitary tumors. In line with the present findings, Woods and Thompson (2008)
[22] and Joshi et al. (2022) [11] have previously reported a higher risk
of permanent DI after surgery for craniopharyngioma compared with surgery for
pituitary tumors. This is most likely because the suprasellar site of
craniopharyngiomas often demands more comprehensive surgery and can involve
resection of the pituitary stalk and hypothalamic structures [11]
[22]
[23]. Postoperative DI is
believed to arise from damage to the magnocellular neurons, which are connecting
the supraoptic and ventricular nuclei in the hypothalamus with the posterior
pituitary via the pituitary stalk [23].
The degree of AVP deficiency could probably be affected by the degree of damage
to these structures, which may explain why patients with craniopharyngioma
required higher doses than patients with pituitary tumors. Moreover, the
patients with craniopharyngioma had a higher percentage of GH deficiencies, a
lower age median, and a longer disease duration compared to patients with
pituitary tumors, which may contribute or explain the observed findings.
Strengths and limitations
The strengths of this study include the size of the study population considering
the rarity of DI. Though this study also has limitations primarily caused by the
retrospective design and the lack of confirmatory water deprivation test in the
majority of patients.
Another possible source of error is the conversion of nasal and sublingual doses
to the equivalent oral doses of desmopressin, though this source is inevitable
when comparing different forms of administration, and the calculated dose
requirements are associated with some uncertainty. Another important confounder
is that some patients do not have intact thirst, which other studies have found
a higher risk of hyper- and hyponatremia [21]. There may be an underlying confounder that affects whether
certain patient groups are treated with either one or the other form of
administration, which increases the risk of selection bias. Ideally, it would be
necessary to examine the sodium concentrations in the same patients before and
after they switch from one to the other form of administration. Also, data about
comorbidities associated with hyponatremia such as chronical heart-, liver- and
kidney-diseases were not considered. Finally, it is important to mention that
the prescribed doses in the patients’ files may not represent the
optimal dose for each patient. Taking this into account would require a more
qualitative study, which could also investigate the patient’s perception
of the effect.
Conclusion
This study found that the patients in the congenital group required higher
desmopressin doses compared to the patients in the group with acquired DI, a finding
limited by the low number of patients with congenital DI. There were no association
between BMI and desmopressin dose requirement in the full sample, nor between the
risk of hyponatremia and the mode of administration. Nonetheless, the current study
suggests that higher body weight, younger age, and a larger number of years living
with DI were associated with higher dose requirements in patients treated with oral
tablets. Also, patients with craniopharyngioma received higher doses of desmopressin
compared to patients with pituitary tumors.
