cerebral palsy - sialorrhea - child - drug therapy - atropine
paralisia cerebral - sialorreia - criança - quimioterapia - atropina
Drooling is the involuntary loss of saliva and buccal content[1],[2] and it usually occurs in infants. Drooling is abnormal in children older than four
years and it often persists in children with neurological disorders with neuromuscular
incoordination of swallowing, and intelectual disabilities such as cerebral palsy
(CP)[1].
The prevalence of drooling in CP is not often studied[1]. Some authors report a prevalence between 10% and 58%[3],[4],[5],[6]
. The drooling in CP children is not caused by hypersalivation, but by oral motor dysfunction,
dysphagia and/or by an intraoral sensitivity disorder[1],[5],[7],[8]. Drooling affects the lives of CP children and their families, both clinically and
socially. Anterior drooling is the unintentional loss of saliva from the mouth. It
may lead to psychosocial consequences for children and for their families such as
social isolation, the constant need to remind the individual to swallow the saliva,
as well as the need to clean up the excess saliva in the mouth, chin and other areas,
and change and wash towels and clothes. There are also physical consequences such
as perioral infections and damages to the dentition[1],[6],[8]. Posterior drooling occurs whenever the saliva slips from the tongue to the pharynx.
It poses a saliva aspiration risk, which may not be diagnosed before the development
of significant lung injury[1],[6].
The drooling severity and impact may be assessed through objective or subjective methods[9]. The objective methods include the measurement of the salivary flow and the direct
observation of the loss of saliva; however, these are complicated and/or invasive
methods. Subjective scales are useful and appropriate methods to measure changes in
drooling, assessing the impact on families, caregivers and on the individuals themselves[9],[10].
Some drooling treatment modalities can be used in CP such as training for sensory
awareness and oral motor skills; oral, transdermal and sublingual anticholinergic
drugs; application of botulinum toxin; and surgical management[8],[11],[12],[13]. Glycopyrrolate, benztropine, scopolamine and trihexyphenidyl are the most-used
systemic anticholinergic drugs. They induce a significant reduction in saliva flow
and their effectiveness has been confirmed in several studies[14],[15],[16],[17],[18],[19]. On the other hand, they can lead to side effects such as vomiting, diarrhea, irritability,
mood changes and insomnia.
Although atropine sulfate was acknowledged as effective many years ago, it never received
wide acceptance in the treatment of chronic drooling. Its mechanism of action is by
blocking the muscarinic receptors (M3) in the salivary glands, leading to reduced
saliva production[17]. Some articles have reported its use in the treatment of drug-induced drooling[20],[21],[22] and in Parkinson’s disease patients[23]. The only article referring to its use in treating drooling in children or adolescents
reported the case of a successfully-treated 14-year-old boy with metachromatic leukodystrophy[17]. There is only one prospective, randomized, placebo-controlled double-blind study
that has investigated the use of sublingual atropine sulfate to treat drooling. The
cohort comprised 22 adult subjects with upper gastrointestinal tract cancer and the
atropine had no effect on those patients in comparison to the placebo[24].
There is no published study assessing the use of atropine sulfate to treat drooling
in CP children.
The aim of the current study was to report the effect of using sublingual atropine
sulfate to treat drooling in CP children and adolescents by comparing the results
of the Drooling Impact Scale (DIS). Our hypothesis was that there would be a reduction
in the DIS score after the use of atropine sulfate, as well as few side effects.
METHODS
Participants
All children and adolescents treated at a neurorehabilitation center in Rio de Janeiro
(Brazil) were assessed for eligibility. The inclusion criteria were: 1) CP diagnosis
according to the International Executive Committee for the Definition of Cerebral
Palsy[25]; 2) presence of drooling as defined by Blasco[2]; 3) presence of clinical and/or social damage for the children, followed or not
by the feeling in the family of overload caused by drooling; 4) ages between two and
17 years; 5) weight greater than or equal to 10 kg; and 6) normal electrocardiogram.
The following criteria were interpreted as losses: 1) presence of side effects; 2)
irregular use of atropine sulfate; 3) discontinuation in the use of atropine sulfate.
Thirty-three patients met the inclusion criteria. Eight individuals met the loss criteria,
one due to irregular use of atropine sulfate, three due to discontinuation in the
use of atropine sulfate, and four due to side effects. The final sample comprised
25 patients. [Table 1] shows the participants’ sociodemographic and clinical characteristics.
Table 1
Patient characteristics (n = 25).
|
Gender (male / female)
|
13 / 12
|
|
Mean age (year) ± SD
|
8.6 ± 4.2
|
|
Mean weight (Kg) / Minimum – Maximum (Kg)
|
19.5 / 10.9 – 37.5
|
|
GMFCS, n (%)
|
|
I
|
Zero (zero)
|
|
II
|
2 (8)
|
|
III
|
1 (4)
|
|
IV
|
7 (28)
|
|
V
|
15 (60)
|
|
Comorbidities, n (%)
|
|
Dysphagia
|
15 (60)
|
|
GERD
|
13 (52)
|
|
ID
|
24 (96)
|
|
Epilepsy
|
17 (68)
|
SD: standard deviation; GMFCS: gross motor function classification system; GERD: gastroesophageal
reflux disease; ID: intellectual disability.
Ethics
The current study was approved by the Research Ethics Committee of the SARAH Network
of Rehabilitation Hospitals (Certificate of Submission for Ethics Assessment 48300015.0.0000.0022).
The informed consent form was signed by the patients and their caregivers.
Data collection
The data were collected by five pediatricians (including the author) of the neurorehabilitation
center, who were trained to homogeneously perform the task and were also responsible
for prescribing the atropine sulfate. The following sociodemographic and clinical
variables were analyzed in addition to the results of the DIS: age, gender, weight,
and the Gross Motor Function Classification System[26]. The following comorbidities were taken into consideration: 1) dysphagia was defined
as the presence of oral (difficulty in receiving food bolus, extraoral loss of food,
suction disorder, increased oral transit time, food residue) and/or pharyngeal phase
symptoms (tachypnea and/or dyspnea, coughing and/or gagging, throat clearing, nasal
regurgitation during or immediately after feeding); 2) gastroesophageal reflux disease
(GERD) defined as the presence of vomiting, regurgitation, nausea, refusal of solid
food, belching and hiccups during or immediately after feeding; and 3) intellectual
disability as defined by the criteria of the Diagnostic and Statistical Manual of
Mental Disorders V[27], and epilepsy as defined by the criteria of the International League Against Epilepsy[28].
The Drooling Impact Scale
The current study used a Portuguese translated, but not validated in Brazil, version
of the DIS (its use was permitted by the author of the original scale). Although not
yet validated, the version of the scale translated into Portuguese had already been
used in clinical practice for several months in our hospital and, in our evaluation,
the families easily understood each question. The DIS has been specifically designed
to quantify and longitudinally assess the short/medium-term benefits of interventions
for drooling and changes in the impact caused by drooling, on children with neurodevelopmental
disorders, including CP and intellectual disabilities, and on their caregivers. The
items comprising the scale (described in the [Table 2]) are constructed as a 10-point scale. The DIS can be answered by the caregiver or
by the patient, and it may be also annotated by the interviewer[11].
Table 2
Drooling impact scale items.
|
1- How frequently did your child dribble?
|
|
2- How severe was the drooling?
|
|
3- How many times a day did you have to change bibs or clothing due to drooling?
|
|
4- How offensive was the smell of the saliva on your child?
|
|
5- How much skin irritation has your child had due to drooling?
|
|
6- How frequently did your child's mouth need wiping?
|
|
7- How embarrassed did your child seem to be about his/her dribbling?
|
|
8- How much do you have to wipe or clean saliva from household items, e.g. toys, furniture,
computers?
|
|
9- To what extent did your child's drooling affect his or her life?
|
|
10- To what extent did your child's drooling affect you and your family's life?
|
Atropine sulfate
There are no specific atropine sulfate formulations for sublingual use; thus, ophthalmic
drops of 0.5% were used. The prescribed dose consisted of one sublingual drop administered
three times a day at six-hour intervals for patients weighing between 10 kg and 19
kg and two sublingual drops administered three times a day at six-hour intervals for
patients with a weight equal to or greater than 20 kg. These doses were determined
from the single article on the use of atropine sulfate to treat drooling in an adolescent,
in which there was a good tolerability level[17].
There are no specific studies on the bioavailability of 0.5% sublingual atropine sulfate
drops. Rajpal et al. published a study in which a preparation of 2% atropine sulfate
was formulated (a concentration four times greater than that employed by us) and administered
by sublingual injection, not by drops, to adult individuals. All the volunteers showed
early symptoms of atropinization, such as dry mouth, blurring vision, and thirst,
15 to 30 minutes after the injection[29].
Study design and interventions
This was a non-controlled open clinical trial conducted between July 2013 and June
2014. All patients who met the inclusion criteria were evaluated on the DIS before
the beginning of the treatment. The patients started using 0.5% sublingual atropine
sulfate and returned after 30 days of effective use of the substance. Patients who
met the loss criteria were excluded from the study. The remaining patients were included
in the final sample and evaluated on the DIS again.
Statistical analysis
The SPSS software version 20 (IBM Corp.) was used for statistical analysis. Descriptive
statistics were used to analyze the sociodemographic and clinical variables. For the
analytical statistics, the Kolmogorov-Smirnov test and graphical analyses were applied
to the pre- and post-treatment DIS samples and both showed normal distribution. The
pre- and post-treatment DIS scores were considered as continuous variables and the
samples were considered as paired because the same sample was evaluated before and
after the atropine sulfate treatment. Thus, the paired t-test was used in the following
analyses: 1) comparison between the total pre- and post-treatment DIS scores; 2) analysis
of the total scores for each pre- and post-treatment DIS question; 3) comparison between
the means of intervening variables in “Yes” (presence) and “No” (absence) samples
of each comorbidity in relation to the pre-treatment DIS score (considered as a drooling
severity marker) and the difference between the mean pre- and post-treatment DIS scores
(considered as improvement the level marker related to the use of atropine sulfate).
The significance level of 95% (p < 0.05) was adopted in all analyses.
RESULTS
Comparison between the total pre- and post-treatment DIS scores
[Table 3] shows the reduction in the mean pre- and post-treatment DIS scores. The difference
between these means reached statistical significance (p < 0.0001).
Table 3
Comparison between the total pre- and post-treatment DIS scores. n = 25.
|
Variables
|
Minimum
|
Maximum
|
Mean
|
SD
|
p-value
|
|
DIS pre
|
25
|
86
|
61.80
|
13.92
|
|
|
DIS post
|
12
|
61
|
25.60
|
11.37
|
|
|
Difference DIS pre – DIS post
|
6
|
60
|
36.20
|
16.59
|
< 0.0001
|
SD: standard deviation; DIS: drooling impact scale; DIS pre: pre-treatment DIS; DIS
post: post-treatment DIS.
Analysis of the total scores of each pre- and post-treatment DIS question
The analysis of the difference between the mean score of each pre- and post-treatment
DIS question is summarized in [Table 4]. It shows a statistically significant reduction in all questions (p < 0.0001 in
questions 1, 2, 3, 6, 8, 9 and 10; p < 0.003 in question 4), except in questions 5
and 7.
Table 4
Analysis of the total scores of each pre- and post-treatment DIS question.
|
Difference (DIS pre – DIS post)
|
Mean
|
SD
|
p-value
|
|
1- Drooling frequency
|
4.68
|
2.268
|
< 0.0001
|
|
2- Drooling severity
|
4.32
|
2.212
|
< 0.0001
|
|
3- Frequency of bibs or clothing changes
|
36.80
|
25.45
|
< 0.0001
|
|
4- Saliva's smell offensiveness
|
1.80
|
2.708
|
< 0.003
|
|
5- Skin irritation
|
0.20
|
0.577
|
0.96
|
|
6- Frequency of mouth wiping
|
5.32
|
2.545
|
< 0.0001
|
|
7- Embarrassment caused by drooling
|
1.44
|
25.99
|
0.11
|
|
8- Frequency of wiping saliva from household items
|
42.40
|
29.48
|
< 0.0001
|
|
9- Impact of drooling in child's life
|
49.60
|
30.48
|
< 0.0001
|
|
10- Impact of drooling in family's life
|
55.60
|
30.29
|
< 0.0001
|
DIS: drooling impact scale; SD: standard deviation; DIS pre: pre-treatment DIS; DIS
post: post-treatment DIS.
Comparison between the means of intervening variables
In [Table 5], the absence of GERD was correlated with the greater difference between the mean
scores in the pre- and post-treatment DIS. It reached statistical significance (p
< 0.024) and so did the absence of epilepsy (p < 0.02). In other words, the samples
from patients without GERD and epilepsy reached statistically significant improvement
levels due to the use of atropine sulfate. The absence or presence of any of the comorbidities
did not influence the drooling severity since no statistically significant results
were found separately in the mean pre-treatment DIS scores for any absence or presence
of any of the studied comorbidities.
Table 5
Comparison between the means of intervening variables.
|
Variable
|
DIS pre
|
Difference DIS pre – DIS post
|
|
|
|
Mean
|
p-value
|
Mean
|
p-value
|
|
Dysphagia
|
|
Yes
|
59.47
|
0.649
|
32.33
|
0.158
|
|
No
|
66.75
|
42
|
|
GERD
|
|
|
|
|
|
Yes
|
58.85
|
0.279
|
29.15
|
0.024
|
|
No
|
65
|
43.83
|
|
ID
|
|
Yes
|
61.5
|
-
|
35.63
|
-
|
|
No
|
69
|
50
|
|
Epilepsy
|
|
Yes
|
59.47
|
0.23
|
35.63
|
0.02
|
|
No
|
66.75
|
47.13
|
DIS: drooling impact scale; DIS pre: pre-treatment; DIS post: post-treatment; GERD:
gastroesophageal reflux disease; ID: intellectual disability
Side effects
Side effects were found in four out of the 33 patients who started the study (12,1%)
and their respective frequency occurred as follows: fever and flush (1); irritability
(1); flush and irritability (1); flush and angioedema (1).
DISCUSSION
To our knowledge, this is the first study that reports the use of sublingual atropine
sulfate to treat drooling in CP children and adolescents.
The indication of any type of drooling treatment in CP patients must take into account
their social and family contexts. Thus, one should indicate efficient and more specific
methods that cause less overload to each patient/family. The efficacy of some of the
available treatment modalities have been proven; however, they have features that
hinder the patients’ access to these techniques. The oral, transdermal, or sublingual
use of anticholinergic drugs has the advantage of not requiring medical and nursing
apparatus, specific equipment, sedation or anesthesia in order to be applied.
The atropine sulfate was chosen in the current study due to its originality in the
treatment of drooling in CP patients and to the easy access to the drug. However,
one disadvantage is its transient effect and, consequently, the need for its continuous
use of three doses a day in order to maintain its effect.
Atropine sulfate use was associated with a statistically significant reduction in
the DIS score (p < 0.0001) in this CP population. Other studies have demonstrated
the benefit of other anticholinergic drugs; however, the current study achieved a
better safety profile (12.1% of the patients reported side effects). Mier et al.
[15] showed that glycopyrrolate effectively controlled the CP patients’ drooling; however,
20% of the children had side effects severe enough to discontinue the use of the drug.
Zeller et al.[19]reached percentages of response to oral glycopyrrolate with a peak of 56.7% in the
16th week. They found several side effects in 20.4% of the patients. Mato Montero et al.[16] found significant drooling reduction (p < 0.005) in a transdermal scopolamine group
in comparison to a placebo group, in which 13.3% of patients were excluded from the
study due to severe side effects. Camp-Bruno et al.[14] found a significant drooling decrease in their benztropine group in comparison to
the placebo group, but severe cholinergic side effects required the discontinuation
of the drug in 12% of the patients. Carranza-del Rio et al.[18] concluded that most of their dystonia CP patients (96%) reported some improvement
in involuntary movements and/or drooling; however, 69.3% of them showed side effects.
Among the several anticholinergic drugs, sublingual atropine sulfate seems to have
a more local and lesser systemic effect. This feature may have contributed to a better
safety profile.
The DIS questions assess ten different drooling-influence parameters in the lives
of the children and their families. The current study individually analyzed the effect
of atropine sulfate on each parameter by analyzing the difference between the means
of each question in the pre- and post-treatment DIS. This analysis showed statistically
significant reduction in all questions, except in questions 5 and 7. Question 5 relates
to skin irritation, and its frequency was low among the patients in the sample. Question
7 concerns how embarrassed the patient feels due to drooling; this feeling was reduced
by the presence of intellectual disability, which had a high incidence in the sample.
Both situations led to low pre-treatment DIS scores in these questions and, consequently,
to a statistically significant reduction in the improvement potential.
The fact that only the samples from patients with no GERD and epilepsy achieved statistically
significant improvement levels due to the use of atropine sulfate could be related
to the clinical perception that the presence of GERD (which stimulates the parasympathetic
route and saliva production) and epilepsy (due to the need to use certain anticonvulsants)
could increase drooling severity and reduce the therapeutic response to atropine.
However, we did not come to the same conclusion as we did not find statistically significant
results in the mean pre-treatment DIS scores (drooling severity marker) for any absence
or presence sample of any of our studied comorbidities.
The use of sublingual atropine sulfate seems to be safe and is related to a reduction
in DIS scores, which suggests efficacy in the treatment of drooling in CP children
and adolescents. However, since it is a non-placebo-controlled open clinical trial,
our results must be interpreted with parsimony and replicated in randomized, placebo-controlled
studies with larger numbers of participants.
