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© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
Introduction
Obstructive sleep apnoea (OSA) is the most common form
of sleep-disordered breathing (1), defined as a clinical
condition in which there is intermittent and repeated
upper airway (UAW) collapse during sleep which results
in irregular breathing at night and, typically, excessive
sleepiness during the day.
Although the first empirical description is attributed
to Charles Dickens in 1836, OSA and its associated
polysomnographic ndings was dened in 1965 by Jung and
Kuhlo (2) in Germany and Gastaut (3) in France.
The prevalence of OSA is a worldwide burden on public
health, it affected 4% of middle aged men and 2% of middle
aged women in the United States in the early 1990’s (4), but
with an increase in obesity rates prevalence is now 10%
of the 30-49 year-old men and 3% of the 30-49 year-old
women (5).
OSA is associated with signicant co-morbidities, which
include hypertension (6), ischaemic heart disease (7),
stroke (8), congestive heart failure (9), obesity and
metabolic syndrome (10), and diabetes (11). It has been
recognised as a significant cardiovascular risk. Treatment
of OSA is not only provided to control day- and night-
time symptoms but also to reduce the overall long-term
cardiovascular risks.
According to current guidelines (12), treatment with
Review Article
Emerging technology: electrical stimulation in obstructive sleep
apnoea
Martino F. Pengo1,2, Joerg Steier1,3,4
1Guy’s and St. Thomas’ NHS Foundation Trust, Lane Fox Respiratory Unit/Sleep Disorders Centre, London, UK; 2Department of Medicine
(DIMED), University of Padua, Italy; 3King’s College London School of Medicine, London, UK; 4King’s Health Partners, London, UK
Correspondence to: Dr. Martino F. Pengo. Clinical Research Fellow, King’s College London, Guy’s and St. Thomas’ Hospital NHS Foundation Trust,
Lane Fox Respiratory Unit/Sleep Disorders Centre, Nufeld House, Great Maze Pond, London SE1 9RT, UK. Email: martino.pengo@gstt.nhs.uk.
Abstract: Electrical stimulation (ES) of the upper airway (UAW) dilator muscles for patients with
obstructive sleep apnoea (OSA) has been used for several decades, but in recent years research in this eld
has experienced a renaissance; the results of several studies have triggered a steady rise in the interest in this
topic. Prospective trials, although still lacking a sham-controlled and randomised approach, have revealed
the potential of ES. Hypoglossal nerve stimulation (HNS) leads to a signicant reduction in the apnoea-
hypopnoea index and the oxygen desaturation index (ODI). There are similar results published from
feasibility studies for transcutaneous ES. A limitation of HNS remains the invasive procedure, the costs
involved and severe adverse events, while for the non-invasive approach complications are rare and limited.
The limiting step for transcutaneous ES is to deliver a sufcient current without causing arousal from sleep.
Despite the progress up to date, numerous variables including optimal stimulation settings, different devices
and procedures remain to be further dened for the invasive and the non-invasive method. Further studies
are required to identify which patients respond to this treatment. ES of the UAW dilator muscles in OSA has
the potential to develop into a clinical alternative to continuous positive airway pressure (CPAP) therapy. It
could benet selected patients who fail standard therapy due to poor long-term compliance. It is likely that
international societies will need to review and update their existing guidance on the use of ES in OSA.
Keywords: Transcutaneous genioglossal stimulation; hypoglossal nerve stimulation (HNS); implantable device;
upper airway (UAW); oxygen desaturation; sleep-disordered breathing
Submitted Mar 27, 2014. Accepted for publication Apr 01, 2014.
doi: 10.3978/j.issn.2072-1439.2014.04.04
2Pengo and Steier. Electrical stimulation in obstructive sleep apnoea
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
continuous positive airway pressure (CPAP) is indicated
in patients with moderate-severe OSA, and a mandibular
advancement device (MAD) should be considered in
patients with mild symptomatic OSA. However, although
CPAP provides the best effective treatment, it is not
well tolerated by all patients over longer periods and the
adherence rate is limited and inuenced by symptoms and
disease severity; approximately 2/3 of patients who should
be on CPAP continue with the treatment at ve years (13).
Thus, alternatives to CPAP are needed for patients who fail
this treatment and who continue to experience symptoms
with associated cardiovascular risks.
Since 2011, a technology has emerged as a rapidly
developing and promising treatment alternative in OSA.
Electrical stimulation (ES) has been used to activate the
dilator muscles of the UAW and this might enable patients
to maintain a patent UAW while asleep. The different
methods that are currently used in a research or clinical
scenario, ‘pros’ and ‘cons’ and the clinical relevance of these
novel treatments will be discussed.
Pathophysiology of obstructive sleep apnoea
The anatomy of the UAW is complex as it includes
different groups of muscles that are involved in different
physiological functions. The UAW can be divided into
three compartments: (I) the naso-pharynx (epi-pharynx)
whose function is mainly respiratory; (II) the oro-pharynx
which has respiratory, swallow and reflex functions; and
(III) the laryngo-pharynx (hypo-pharynx) whose functions
include speech, swallow and respiratory function.
Neural drive to the UAW dilator muscles falls with sleep
onset. The reduced activity of the UAW dilators results in
a reduced neuromuscular tone with a narrowed pharyngeal
lumen, which can lead to a complete collapse of the airway
via the Bernoulli effect (14). This, in turn leads to snoring
and, with complete obstruction, to sleep apnoea.
Remmers et al. described repetitive UAW occlusion
in sleep (15) and examined the relationship between the
genioglossal electromyogram (EMG) and the pharyngeal
pressure demonstrating that airway occlusion occurred
when the negative pharyngeal pressure exceeded the
genioglossus force, a so-called ‘balance of forces’ (Figure 1).
More recently, other theories have tried to explain sleep
apnoea with an impaired neuromuscular response during
UAW occlusion and therefore a failure to compensate and
restore the airway patency. Mezzanotte et al. (16) have
demonstrated that with sleep onset pharyngeal collapse is
‘Balance of forces’
Central nervous system
Afferent/efferent signals
Upper airway dilator muscles Forces promoting patencyForces promoting closure
Physiological features
•Tonic and phasic upper airway
dilator activity
•Wakefulness
Clinical features
•Lean body
•Low neck circumference
•Low Mallampati score
•Non-supine posture
Physiological features
•Negative intraluminal pressure
•Surface tension
•Gravity
•Sleep
Clinical features
•Obesity
•Increased neck circumference
•Increased Mallampati score
•Supine posture
Confounders
Age
Gender
Co-morbidities
Figure 1 Simplied model of the ‘balance of forces’, factors that promote closure or patency of the upper airway. During sleep the central
drive to activate the upper airway dilator muscles is diminished, which leads to an imbalance in favour of the forces promoting closure of the
upper airway, other confounders might ‘tip the balance’ due to an older age or male gender.
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Journal of Thoracic Disease, Apr 01, 2014
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
associated with a loss of genioglossus muscle (GG) tone.
Another theory hypothesises about structural defects
that increase UAW collapsibility and predispose to airow
obstruction during sleep. This hypothesis has been studied
by several authors (17) who showed the importance of
rostral movements of the trachea during lung deflation,
that are associated with reductions in longitudinal tension
within the airway that can, in part, explain the pathogenesis
of OSA.
Following on from the rst descriptions of OSA multiple
studies have attempted to describe the activity of the most
important pharyngeal dilator muscles, in particular the
activity of the genioglossus (18). Anatomical features and
mechanical narrowing of the UAW play an important role
in OSA but functional factors are similarly fundamental
contributors to UAW patency (Figure 1).
Oliven’s group could show that enhanced UAW muscle
activity during ES decreases UAW resistance in an isolated
UAW model confirming the role of functional factors
(19,20). Van de Graaff and colleagues could show that ES
of the UAW dilator muscles could shift the hyoid bone
anteriorly confirming the contributory role of the UAW
anatomy (21).
Non-invasive methods
Submental transcutaneous electrical stimulation (ES)
Treating the functional loss of the neuromuscular tone
with sleep onset and the contributing anatomical factors
at the same time in order to keep the UAW patent during
sleep is hypothetical way to treat the cause of OSA. First
studies on transcutaneous ES were performed by Miki et al.
with promising results (22). They studied six patients with
full polysomnography on and off electrical transcutaneous
stimulation using 10 mm bipolar electrodes to the skin of
the patients in the submental region and stimulated the
patients using an apnoea demand-type stimulator. When
apnoeas lasted for longer than 5 s the device delivered ES
with a frequency of 50 Hz and a voltage of 15-40 V until
breathing resumed or after 10 s at the longest. This kind of
treatment resulted in a signicant reduction of the apnoea
index and the apnoea time per total sleep time.
However, shortly after this study another group could
not conrm these results. Indeed, Edmonds et al. reported
that transcutaneous and submental ES failed to enlarge
the UAW, as observed by computer tomography during
wakefulness, and they were unable to reverse UAW
obstruction using this method in the asleep patient without
causing arousals (23). Similar results were reported by
Decker et al. (24) stating that submental transcutaneous
stimulation led invariably to arousal from sleep.
A few years later, Hida et al. demonstrated the
effectiveness of submental transcutaneous stimulation in
patients with severe OSA (25). They stimulated 13 patients
during an overnight study with ES starting when an apnoea
lasted for five seconds; stimulation was stopped after
ventilation resumed or after a maximum of 20 seconds. In
their study, the apnoea-hypopnoea-index dropped from a
mean of 53.8/h to 6.6/h.
A year later, Guilleminault et al. (26) tested submental
and intra-oral sublingual ES in seven patients with severe
OSA without achieving any benet. They delivered an ad-
hoc stimulation during 15 obstructive respiratory events
testing bilateral and unilateral stimulation; there was no
improvement compared with the baseline measurements.
More recently, two other groups have published
encouraging results using ES in the submental area. Hu
et al. (27) used a biphasic electrical nerve stimulator which
consisted of an electrical pulse generator, an apnoea sensor
and percutaneous electrodes. They enrolled 22 patients
with severe OSA and tested the device during a split night
study. Their device was apnoea-triggered and delivered
ES if no nasal ow was detected for at least 5 s. The mean
respiratory disturbance index (RDI) decreased from 30.9/h
to 12.4/h while stimulation was delivered without signicant
changes in the micro-arousal index.
Steier et al. observed a similar efficacy when testing
transcutaneous and continuous ES of the UAW muscles
delivering a low current in 11 obese patients with
moderate-severe OSA delivered by two large patchy
electrodes (4 cm × 4 cm). After proving the effect of the
stimulation on the contraction of the tongue in healthy
subjects, they showed that the ES reduced the RDI from
and average of 28.1/h to 10.2/h without awakening the
patient, the apnoea hypopnoea index (AHI) was similarly
reduced. The electrical current led to an improved
oxygenation and reduced snoring (Table 1) (28).
None of the studies published on non-invasive ES in
OSA has been a randomised controlled trial. Moreover,
complex and variable stimulation settings make it difcult to
standardise this treatment and to optimise treatment efcacy
(Table 1). Given the diversity of patients and the presence of
various confounders which can affect the effectiveness of the
stimulation (skin impedance, neck circumference and body
mass index (BMI), shape of the UAW) patient selection
4Pengo and Steier. Electrical stimulation in obstructive sleep apnoea
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
Table 1 Summary of the studies on submental transcutaneous stimulation
Study Type of stimulation Type of electrodes Study design N Current Frequency
(Hz)
Pulse width
(μs) Outcomes
Miki et al.
[1989] (22)
Intermittent stimulation
without event association
Surface stimulation
bipolar electrodes
(10 mm diameter)
were attached to the
skin under the chin at
the submental region
Uncontrolled,
open label, single
arm study
6 15-40 V 50 n/a The apnoea index, apnoea time/
total sleep time, longest apnoea
duration, and the number of
times per hour that oxygen
saturation dropped below 85%
decreased significantly on
stimulation
Edmonds et al.
[1992] (23)
Intermittent stimulation
(1-6 seconds on, 1-8
seconds off) for periods
ranging from 5 to 45
minutes followed by
periods of no stimulation
Submental electrodes
in two patients,
submental and
subhyoid electrodes in
six patients
Uncontrolled,
open label, single
arm study
815-39.6 mA 50 n/a Failure to prevent or improve
either sleep-disordered breathing
or sleep architecture
Hida et al.
[1994] (25)
Manual stimulation at
each respiratory event
Two silver electrodes
(10 mm diameter)
attached in the
proximal half of the
submental region
Uncontrolled,
open label, single
arm study
13 5-30 V 100 n/a Reduction in apnoea index,
improvement in apnoea duration
and oxygen saturation
Guilleminault
et al. [1995] (26)
Manual stimulation at
each respiratory event for
15 events
6 electrodes fitted
in a MAD for intra-
oral stimulation and
bilateral electrodes
each side for
submental stimulation
Uncontrolled,
open label, single
arm study
73-6 mA
(10-20 V)
50 80 No changes in number of
apnoeas or oxygen saturation.
Hu et al.
[2008] (27)
Triggered stimulation
(apnoea sensor) after 5 s
of no oronasal airflow.
Submental electrodes Uncontrolled,
open label, single
arm study
22 12-80 V 50 n/a Reduction of RDI, amelioration of
oxygen saturation
Steier et al.
[2011] (28)
10 minutes continuous
bilateral stimulation
Submental, two 4 cm x
4 cm patches
Uncontrolled,
open label, single
arm study
11 10.1 (3.7) mA 30 250 Reduction of AHI and RDI,
improvement of oxygen
saturation, reduction of snoring
N, number of patients; V, volt; mA, milli-Ampere; Hz, Hertz; n/a, not applicable or not available; MAD, mandibular advancement device;RDI, respiratory disturbance
index; AHI, apnoea hypopnoea index. Data on current indicate the range (in brackets), except for the study by Steier et al. where it indicates mean (standard
deviation).
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Journal of Thoracic Disease, Apr 01, 2014
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
becomes crucial for future trials using this method to
provide a tailored approach and increase the efcacy of this
method. A non-invasive trial of this method to select and
stratify OSA patients into responders and non-responders,
for example during a drug-induced sleep endoscopy (DISE),
could prove to be helpful prior to commencing discussions
about an implanted stimulator.
Invasive methods
Fine wire stimulation
Initial experiments in cats, dogs and rats using direct
stimulation of the GG evoked a muscle contraction and
revealed improvements in the pharyngeal patency; these
results prompted investigators to test this technique in
humans (29-31). Bishara et al. tested ES using Teon-coated
stainless steel electrodes inserted into the genioglossus,
geniohyoid, sternohyoid, and sternothyroid muscles
bilaterally in 16 dogs during UAW obstruction (32).
They could show that stimulation of the genioglossus and
geniohyoid reduced the UAW resistance prior to and during
partial occlusion which was caused by a small rubber balloon
connected to a thin tube that was implanted percutaneously
under the pharyngeal submucosa. More interestingly, they
found that the GG was the most effective dilator muscle
reducing UAW resistance and avoiding airway occlusion.
In addition, changes in head, lower jaw and tongue position
were shown to substantially affect the airway resistance.
This observation adds complexity to the issue of UAW
patency in sleep. In order to maintain a patent airway using
ES the intensity would require an adjustment according to
the airway resistance, influenced for example by the head
posture, but at the same time changes in the electrical
current should not cause arousal from sleep.
Studies on selective intra-muscular stimulation of the
hyoglossus, styloglossus and GGs (33) found that there
are differences in the response and the contraction of
the muscles which depend on the site of the stimulation.
Stimulation near the proximal hypoglossal nerve can cause
a closure of the upper airway while distal hypoglossal
stimulation induces a contra-lateral tongue deviation and
variable degrees of airway opening during sleep (33). This
might be an explanation for the variable response of the
muscles during ES; it confirms that different stimulation
sites will recruit different groups of muscle bres. Proximal
hypoglossal stimulation will reach the lingual muscles,
pulling the base of the tongue posteriorly and distal
stimulation will reach the genioglossus and moves the
tongue anteriorly to sustain UAW patency.
Hypoglossal nerve stimulation (HNS)
Following publication of the results of initial experimental
studies on UAW dilator muscle stimulation in OSA patients
(23,34,35) several research groups started to test the
possibility of stimulating the muscle via the hypoglossal
nerve. A problem had arisen from the previous observations,
stimulating a single protrusor muscle like the GG could
result in the antagonistic activation of other neck and
tongue muscles which could evoke an antagonistic effect
on airway patency. However, stimulating the hypoglossal
nerve could also lead to the stimulation of multiple tongue
muscles, which could lead to a synergistic effect and a
favorable patency of the UAW (35).
Since the beginning of the new millennium several
studies have been published that demonstrate the effect of
HNS in patients with OSA with consistent results in terms
of effectiveness but, until recently, not in terms of patient
safety (36-38). Different types of invasive stimulators were
used with different specifications and stimulation settings
(Table 2). However, most systems included a circumferential
nerve cuff electrode, a stimulation lead and an implantable
pulse generator.
In 2001, Schwartz et al. (39) published a pilot study on
HNS on eight patients with OSA in whom a stimulator
device (Medtronic Inc, Minnesota, MN/USA) was
implanted and placed in an infra-clavicular subcutaneous
pocket to deliver an inspiratory-triggered stimulation. They
followed patients for a 6-month period and showed that the
AHI had improved by 55-65% (Table 2).
More recently, Schwartz et al. tested a slightly different
approach (37) in an observational, non-randomised and
uncontrolled study using an implantable device (HGNS,
Apnex Medical Inc, St Paul, MN/USA) delivering triggered
stimulation to a group of 30 patients with an AHI greater
than 20/h. This study revealed an improved inspiratory
airow that was dose-dependent on increasing stimulation
intensity.
Eastwood et al. (38) published a single-arm open label
study using the same device (HGNS, Apnex Medical Inc.,
St Paul, MN/USA) on 21 patients with moderate-severe
OSA. At 6-month follow up the AHI had decreased by 55%
with a significant improvement in daytime symptoms, the
Epworth Sleepiness Scale score (ESS) was 12.1 (4.7) points
at baseline and 8.1 (4.4) points at six months’ (P<0.001).
6Pengo and Steier. Electrical stimulation in obstructive sleep apnoea
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
Table 2 Summary of the studies on hypoglossal nerve stimulation
Study Sponsor Type of
stimulation Design of the study N Current Frequency
(Hz)
Pulse width
(μs) Main findings Reduction in
mean AHI
Percentage
reduction
Schwartz et al.
[2001] (39)
Inspire I,
Medtronic
Inc.
Triggered
inspiratory
stimulation
with 1
sensing lead
Non randomised,
uncontrolled
prospective study
8 2.2-3.0 V 33.9-37.7 94.3-110.5 REM and NREM AHI
reduction and improvement
in nocturnal oxygen
saturation after 6 months
(means are averaged over
the 1-, 3- and 6-month follow
up nights)
NREM AHI
from 52
[20.4]/h to
22.6 [12.1]/h
–56.5%
REM AHI from
48.2 [30.5]/h to
16.6 [17.1]/h
–65.5%
Eastwood et al.
[2011] (38)
Apnex
Medical Inc.
Triggered
stimulation
with 2
sensing leads
Single arm open
label study
21 n/a n/a n/a Improvements of
symptoms and AHI after 6
months
AHI from 43.1
[17.5]/h to
19.5 [16.7]/h
–54.7%
Schwartz et al.
[2012] (37)
Apnex
Medical Inc.
Triggered
stimulation
with 2
sensing leads
Non randomised,
uncontrolled
prospective study
30 0-4 mA
(variable)
40 (fixed) 60-90
(variable)
Increase in inspiratory
airflow with increasing
stimulation intensity
n/a n/a
Van de Heyning
et al. [2012] (40)
Inspire II,
Medtronic
Inc.
Triggered
inspiratory
stimulation
with 1
sensing lead
Open prospective
studies (part 1: broad
selection criteria, part
2: using selection
criteria derived from
the experience)
22 (part1)
8 (part 2)
n/a n/a n/a Improvement of AHI,
daytime symptoms and
quality of life at 6 months
AHI from 38.9
[9.8]/h to 10.0
[11.0]/h
–74.3%
Mwenge et al.
[2012] (36)
ImThera
Medical Inc.
Cyclical, non
triggered
stimulation
Open label, single
arm study
13 n/a n/a n/a Improvement of AHI and
mean oxygen saturation at
12 months
AHI from 45
[18]/h to 21
[17]/h
–53%
Strollo et al.
[2014] (41)
Inspire,
Medtronic Inc.
Triggered
inspiratory
stimulation
with 1
sensing lead
Non randomised,
uncontrolled trial
with randomised
withdrawal study in
responders
126 n/a n/a n/a Improvement of AHI
(median from 29.3/h to
9.0/h which equals 68%),
ODI (reduction in median
70%), daytime symptoms
and quality of life at
12 months
AHI from 32.0
[11.8]/h to
15.3 [16.1]/h
–52.1%
N, number of patients; V, volt; mA, milli-Ampere; Hz, Hertz; n/a, not applicable or not available; REM, rapid eye movement; NREM, not rapid eye movement; AHI, apnoea
hypopnoea index; ODI, oxygen desaturation index. All data on the AHI are presented as mean and (standard deviation) and the percentage of reduction is calculated from
the raw data.
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© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
However, at least one adverse event related to the
implantation procedure or related to the treatment occurred
in 71% and 67% of the patients, respectively.
Mwenge et al. (36) undertook a similar study to Schwartz
et al. (37) but they used a different implantable system
(ImThera Medical Inc, San Diego, CA/USA) which consisted
of an implanted pulse generator and a multi-electrode
stimulation lead. The device was implanted in 13 patients
with OSA and the treatment achieved a reduction of the
overall AHI from 45 [18]/h to 21 [17]/h at 12 months, a
reduction of 53%, without observing any changes in the
sleep architecture. An improved symptomatic response
was reported with a reduction in the ESS only at 3-month
follow up [ESS 10.8 (6.2) improved to 6.7 (5.4) points;
P<0.05]. During the follow up period there were multiple
adverse events: one patient had a defective device, two
patients had transient ipsi-lateral tongue hemi-paresis,
one patient underwent surgery but the device could not be
implanted due to a defect, one patient had post-operative
swelling of the neck, in one patient three leads broke, one
patient required a repeat operation and re-implantation and
his replaced lead broke at the end of the study, one patient
had a Twiddler’s phenomenon (electrode displacement)
and all patients experienced one or more technical adverse
event.
In early 2014, Strollo et al. (41) could confirm the
feasibility and effectiveness of invasive HNS in OSA. The
authors implanted a stimulator device (Inspire Medical
Systems, Maple Grove, MN/USA) in 126 patients with
moderate-severe OSA. The patients were assessed at
baseline and after 12-months using a polysomnography.
Responders to the treatment (46 patients) were randomised
in a 1:1 ratio to (I) a withdrawal group in which the device
was turned off; and (II) a therapy maintenance group with
the device turned on. The results demonstrated a reduction
in the median AHI of 68% at 1 year. A symptomatic
improvement in daytime sleepiness and quality of life were
also reported. The withdrawal sub-study conrmed that the
effect was related to ES, the mean AHI in the withdrawal
group increased signicantly compared to the maintenance
group (AHI 25.9/h vs. 8.9/h; P<0.001). Compared to
earlier studies (36) this trial (STAR; 41) revealed that the
intervention was safe with a percentage of serious adverse
events lower than 2%.
However, some issues need to be addressed before this
treatment should be offered in the clinical setting: Firstly,
929 patients were screened for the STAR trial (41), the device
was implanted in only 126 (13.6%) of the screened patients.
The number of responders, defined as a reduction of at
least 50% from baseline in the AHI plus an AHI after one
year of less than 20 events/hour, was 46 out of 126 (36.5%).
Therefore, the number of responders was less than
5% of the screened population. Secondly, there lacked
randomisation and a control group in the first part,
which was acknowledged by the authors. Although it is
difficult to design a suitable control group, there was no
consideration given to a sham group either. Thirdly, it is
worth to consider the cost-effectiveness of this treatment, in
particular when compared to established standard treatment
(CPAP). It is likely that public healthcare will not be able to
fund this treatment for a highly prevalent condition. Lastly,
further studies are required to demonstrate a long-term
effect of this treatment on cardiovascular risks, its impact on
other co-morbidities and whether its efcacy will match the
benet of CPAP.
Discussion
Recent improvements in hardware, methodology and signal
processing have led to a realistic approach of using ES of the
UAW dilator muscles in patients with OSA. This method
might benet selected patients who fail standard therapy (42)
due to poor long term compliance (43). Alternatives to
CPAP therapy are required as the prevalence of sleep apnoea
continues to rise, in line with obesity rates (44). With the
current level of evidence, invasive HNS seems to be more
efficacious than a non-invasive approach, but the invasive
procedure, costs and complications remain a limiting
factors.
Despite the progress up to date, multiple variables
remain unknown. None of the trials in this field was
conducted with a control group. Further, ES might reduce
the severity of sleep-disordered breathing, but it remains an
exclusive achievement of CPAP therapy to entirely abolish
nocturnal apnoeas. A signicant difference in the treatment
is that CPAP effectively treats apnoeas and hypopnoeas via
a ‘pneumatic splint’. In contrast, ES of the UAW maintains
the neuromuscular tone of the UAW dilator muscles.
Rodenstein et al. (45) described the residual effects of
ES on the UAW as a ‘disease-modifying’ concept. They
observed that, when patients enrolled in the trial of HNS
had to stop the treatment because of hardware failures,
they remained free of symptoms for several nights. The
hypothesis that HNS has a residual effect on the UAW
was tested further: At one year follow up, patients who had
experienced a significant improvement in the AHI with
8Pengo and Steier. Electrical stimulation in obstructive sleep apnoea
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
stimulation revealed similar results in the first night off
treatment, the AHI and the micro-arousal index remained
unchanged in the polysomnography. These ndings suggest
that the tonic activity of the HNS may have altered the
neural pattern of the muscular tone of the UAW dilator
muscles. Further studies are required to understand whether
this is a lasting effect and to understand how central
pathways could be altered to impact on UAW patency.
There continues to be a lack of data on long-term
benets of treatment with ES, in particular with respect to
cardiovascular interactions. So far, only Strollo et al. (41)
showed a mild improvement in the diastolic blood pressure
from 81.5 (9.7) to 79.3 (9.5) mmHg (P=0.02) without
signicant changes in systolic blood pressure, heart rate and
BMI.
In order to employ ES in a clinical scenario patient
selection remains important and methods should be
developed to identify responders to this treatment prior to
the intervention and to understand their characteristics; this
would allow to exclude potential non-responders from an
invasive intervention (Table 3). In studies on invasive and
non-invasive ES patients were more likely to respond if they
had moderate-severe OSA, if they were moderately obese
and aged 35-50 years. There are sparse data on women,
older patients and patients with mild OSA. The complexity
of the musculature involved in maintaining UAW patency
adds to the difculty to accurately predict and understand
the effect of ES (46).
UAW collapsibility and, more specifically, the critical
occlusion pressure (Pcrit) of the UAW determine the
likelihood of treatment success; a high Pcrit at baseline (24)
and the magnitude of the reduction of Pcrit during ES (47) are
important predictors. Similarly, the shape of the pharyngeal
lumen seems to be important, a concentric pattern of the
UAW obstruction was associated with a poor response to
ES compared to other patterns (40).
Moreover, Vanderveken et al. (48) evaluated the possible
value of DISE in the assessment of a therapeutic response to
implanted UAW stimulation for patients with OSA. They
found that patients with complete concentric collapse at the
palatal level were less likely to benefit from HNS. DISE
might also be a suitable approach to test non-invasive ES.
Further, titration trials of ES during sleep are required
to determine who responds to this treatment (37) and this
should include an optimisation of the stimulation settings
without causing arousal (current, frequency, pulse width).
Almost all invasive devices deliver triggered stimulation
during inspiration, while transcutaneous stimulation was
commonly used for longer than a single breathe, because
sudden changes in the current are more likely to cause skin
sensation and, subsequently, arousal from sleep. However,
stimulating the muscle specifically during the inspiratory
phase might maximise the response (31). The only study
using non-triggered invasive HNS was published by
Mwenge and colleagues (36) demonstrating that continuous
and non triggered stimulation was similarly effective in
patients with OSA when compared to triggered stimulation.
Currently, there are various different ways to stimulate
the UAW dilator muscles:
(I) Invasively and non-invasively;
(II) Triggered by physiological variables (e.g.,
diaphragm movement, airow, rib cage movement),
intermittent and cyclical or continuous stimulation;
(III) High and low intensity current;
(IV) Nerve and direct muscle stimulation;
(V) Different frequencies of the current (up to 100 Hz);
(VI) Different pulse widths and shapes;
(VII) Unilateral and bilateral location;
(VIII) Unipolar and bipolar current.
The heterogeneity of the different study designs that were
published and the variety of different stimulation settings
leaves in question how best to decide which one of these
techniques will be the most promising approach (Table 4), most
of all because some of the results conict with each other.
Transcutaneous ES has been used intermittently or
continuously, while most invasive devices deliver the
stimulation triggered by an inspiration. In the non-invasive
approach, it remains crucial to avoid skin irritation and
pain. Low currents need to be applied over longer periods
to avoid sudden changes in the current that could awake the
patient. However, in order to avoid fatigue of the muscles
continued stimulation should not be applied for the entire
Table 3 Potential factors associated with treatment failure
High critical occlusion pressure (Pcrit) of the upper airway
Magnitude of the reduction of Pcrit during electrical stimulation
Concentric pattern of the airway obstruction
Lack of titration of electrical stimulation during sleep
Tonsil size 3 or 4
Positional obstructive sleep apnoea
AHI score <20
Morbid obesity (BMI >35)
BMI, body mass index.
9
Journal of Thoracic Disease, Apr 01, 2014
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
night and an optimal on-off regime of the stimulation
remains to be determined.
A compromise in the stimulation frequency needs to
be found to generate a stimulation that can be maintained
over several minutes with sufficient force, but without
experiencing a quick fatigue (50,51). On the other hand,
stimulating the muscle in a specic time-related fashion, as
frequently used for the invasive approach, could maximise
the response during the inspiratory phase (31). However,
it has been shown that invasive (36) and non-invasive (28)
continuous stimulation without a trigger could effectively
reduce the severity of sleep-disordered breathing. Different
stimulation frequencies, wave-forms and voltage of the
stimulation current require further investigations in order
to achieve the most effective response (34); a standardised
stimulation frequency and an optimal wave-form or
amplitude have yet to be dened.
The consideration of specific stimulation settings is
fundamental in order to avoid arousal from sleep. From this
perspective, invasive stimulation of the hypoglossal nerve is
less likely to cause arousal from sleep than the non-invasive
and transcutaneous approach, because lower currents can be
used and skin irritation is largely bypassed. Intra-muscular
stimulation techniques might also be benecial because this
approach allows the recruitment of selected fibres of the
muscle to avoid a sensory activation on the skin receptors
which could lead to an arousal.
A potential limitation to the invasive HNS is the
occurrence of adverse events and side effects. Whilst the
non-invasive approach has limited side effects, adverse
events of the invasive method are more common and often
associated with the surgical procedure. Problems have been
described including anaesthesia and analgesia, surgical risks,
wound infections, haematomas and nerve palsy, broken
leads or incomplete nerve contact.
Invasive and non-invasive techniques share the potential
long-term problems of muscle stimulation which include
muscle fatigue, changes in fibre type composition and
muscle hypertrophy. These effects have not been studied
with these methods so far and, moreover, age (52) and body
weight (53) can affect UAW collapsibility in patients treated
with ES, which requires further examination.
Lastly, the hypoglossal nerve innervates various extrinsic
and intrinsic muscles involved in maintaining UAW
patency (54) and it is important to target the most suitable
bres innervating the muscles with a dilatory effect of the
UAW and to avoid the stimulation of the muscles with
antagonistic effect to the UAW patency (55).
The described progress in the development of this
technique and the stimulator devices will provide us with
a more accurate picture and guidance for the future; more
detailed data and background information on optimal
stimulation settings, titration manoeuvres and operating
techniques (56) will lead to a reduction in the occurrence
of adverse events and an increase in the effectiveness of the
delivered stimulation.
Conclusions and perspectives
ES of the UAW dilator muscles is not a new approach
Table 4 Comparison of the transcutaneous electrical stimulation vs. hypoglossal nerve stimulation
Non-invasive stimulation Hypoglossal nerve stimulation
Current intensity ++ ++
Efficacy + ++
Cost Low High
Long term follow up – +
Effect on cardiovascular parameters – +
Application ++ –
Stimulation Triggered, continuous Triggered, continuous
Target Unspecific Specific
Type of stimulation Bilateral Unilateral
Adverse events Local skin irritation +++
Set up Patches, skin electrodes Surgical intervention
Current level of evidence according to latest guidelines (49) C C
+, more or available; –, less or unavailable.
10 Pengo and Steier. Electrical stimulation in obstructive sleep apnoea
© Pioneer Bioscience Publishing Company. All rights reserved. J Thorac Dis 2014www.jthoracdis.com
to treat OSA, but recent years have seen a renaissance
of this method. Several studies from different groups
have triggered a steady rise in the interest in this topic.
Prospective trials, although still lacking a sham-controlled
and randomised approach, have shown the potential of ES;
currently, there is more evidence for the efficacy of the
invasive approach. However, there are encouraging results
from feasibility studies published for the non-invasive
approach that indicate a similar effect size to HNS. For the
rst time, we experience that this technology might develop
into a clinical alternative to CPAP.
It is likely that in the view of the current evidence
international societies will need to review and update their
guidance and recommendation on the use of ES as a part of
an evidence-based treatment approach in OSA (49). Despite
this the cost-effectiveness and safety of this treatment
remains to be further defined. Moreover, the long-term
acceptance and the cardiovascular impact of UAW dilator
muscle stimulation have not been sufficiently assessed.
Numerous questions remain in order to identify optimal
stimulation settings and to understand the best treatment
approach (Table 5).
Review criteria
References for this review were retrieved from the
PUBMED-MEDLINE databases. Search terms included
“electrical stimulation in sleep apnoea”, “hypoglossal
stimulation”, “genioglossal stimulation”, “alternative
treatment for sleep apnoea” and “implantable device for
sleep apnoea”. Most papers considered were full-text papers
published in English language between 1978 and 2014.
Acknowledgements
Dr. Pengo’s research on electrical stimulation in OSA has
been funded by the Italian Hypertension Society. Dr. Pengo
also wants to acknowledge Prof. GP Rossi for his support.
Competing interests: The authors are part of the study team
that undertake a trial of non-invasive electrical stimulation
of the upper airway dilator muscles in obstructive sleep
apnoea sponsored by Guy’s & St Thomas’ NHS Foundation
Trust and King’s College London School of Medicine, the
NIHR-CLRN South London, and the Italian Hypertension
Society.
Disclosure: The authors declare no conict of interest.
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Cite this article as: Pengo MF, Steier J. Emerging technology:
electrical stimulation in obstructive sleep apnoea. J Thorac Dis
2014 Apr 01. doi: 10.3978/j.issn.2072-1439.2014.04.04
