Aveneu Park, Starling, Australia

Obstructive is an increasing amount of evidence that

Obstructive sleep apnoea (OSA) is a collapse of the upper
airway during sleep which leads to reduced airflow despite efforts to restore
normal airflow. OSA has been implicated as a risk factor in several
cardiovascular complications such as hypertension and heart failure (Xie, et al.,
2017).
The prevalence of OSA in adult men is estimated to be between 3 and 7 % for
adult males and 2 to 5 % for adult women (Punjabi, 2008). As such, treatments
for OSA are important as preventative measures for avoiding cardiovascular
diseases in later life. The primary treatment method for OSA is continuous
positive airway pressure (CPAP), whereby a breathing mask provides positive
pressure to keep upper airways open and enable proper airflow (Eckert, 2018). First developed in
1980s this therapy has been effective in treating the breathing disruptions
associated with OSA. However, the application of this therapy has been
problematic, mainly due to issues of poor patient adherence to CPAP and
developments in the understanding of the contributing factors of OSA. Reportedly
between 46 and 83 % of patients who are prescribed CPAP do not utilise it for
the recommended usage time of 4 hours of nightly usage (Weaver &
Grunstein, 2008).
This presents a significant challenge in effectively treating OSA in the wider
population. The aim of CPAP is to treat the main causative factor of OSA, which
is a narrow or collapsible upper airway tract (Eckert, 2018). However, there is
an increasing amount of evidence that an individual’s susceptibility to OSA can
depend on other factors which are not usually specifically treated. These
factors include upper airway dilator muscles, loop gain and respiratory arousal
threshold (Eckert, et al., 2013). Eckert puts forward
a compelling argument that is central to my opinion that OSA treatment should
move away from the so called “one size fits all” hypothesis and focus more on
implementing tailored, patient-specific therapies.

Upper Airway Dilator Muscles

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The opening of the upper airway tract is maintained with the
activity of the upper airway dilator muscles, such as the genioglossus and the
tensor palitini, which provide strength and support to the pharynx. These
muscle groups are supressed during REM sleep and result in increased
collapsibility of the airway tract. In OSA patients the loss of function of
these support muscles contributes to the high rate of occurrence of apneas
during sleep. A therapeutic treatment that could reverse this pharyngeal
hypotonia could greatly reduce the occurrence of apneas in OSA patients. The
complex nature of the neural circuitry that regulates the control of pharyngeal
muscles has led to difficulties in finding an effective treatment, but studies on
rats have highlighted the role of noradrenergic and muscarinic processes in the
regulation of the pharynx (Chan, et al., 2006) (Torontali, et al., 2014). A recent trial
using desipramine, a tricyclic antidepressant with noradrenergic and
antimuscarinic activity on humans found that the drug reduced upper airway
collapsibility in healthy individuals (Taranto-Montemurro, et al., 2015). A follow up trial
is ongoing to see if the effects are applicable to OSA patients. If successful
then it could present a novel, non-invasive means of treating OSA.

Another potential pharmacological therapy for OSA is
acetazolamide. This drug can potentially correct a respiratory dysfunction that
can contribute the formation of apneas during sleep known as ventilatory loop
gain. Loop gain can be described as the ventilatory response to a disturbance in ventilation ratio (Eckert, 2018). OSA patients are
frequently found to have a high loop gain ratio as their ventilatory response
to even slight changes in CO2 levels is excessive and promotes instability to
the regulation of breathing. This can manifest as large increases in
respiratory rate in response to the narrowing of the airway, followed by a
subsequent decrease in respiratory drive that can cause an apnoea (Wellman, et
al., 2011).
Acetazolamide is a carbonic anhydrase inhibitor that can act as a respiratory
stimulant by inducing metabolic acidosis. By increasing baseline respiratory
rate it may reduce loop gain, promote respiratory stability and reduce OSA
severity in some patients. Experiments by Wellman showed that acetazolamide reduced
loop gain by around 40% in OSA patients, highlighting it as a potential
therapeutic agent for treating OSA.

Respiratory
Arousal Threshold

Arousal from sleep was initially
thought to be a necessary event to restore airway patency in OSA patients.
Closer inspection of the occurrence of the opening of the upper airway tract
and arousal has revealed that not only is arousal not a necessary event in
restoring airflow, but it may in fact be perpetrating the dysregulated
breathing cycles that occur in OSA (Younes, 2004). Younes proposes
that the increased respiratory drive that occurs in sleep apnea is the cause of
these arousals but is also the cause of the recruitment of upper airway dilator
muscles. Arousal may be preventing the occurrence of the recruitment of these
muscle groups to restore airway patency. Hence, preventing or delaying the occurrence
of these arousals may promote respiratory stability by allowing this muscle
recruitment to occur. A low arousal threshold may be a significant contributing
factor to the development of OSA in non-obese patients (Gray, et al.,
2017).
While non-obese patients usually suffer from mild OSA compared to more severe OSA
of obese patients, they are typically less adherent to CPAP treatment and are
challenging to treat as a result. A pharmacological agent that could prove
useful in treating patients with low arousal threshold is trazodone (Eckert, et
al., 2014).
This serotonin antagonist has been shown to increase the arousal threshold in
OSA patients by 30% without reducing upper airway dilator muscle activity. Thus,
by reducing the occurrence of low-threshold arousals respiratory stability is
promoted and the recruitment of dilator muscles may occur uninhibited, although
further research is required to verify this. Nonetheless it presents a
promising therapeutic treatment that could circumvent the issues in treating non-obese
OSA patients who normally are non-compliant with CPAP treatment.

The focus on pharmacological therapies
for OSA is primarily to propose a solution to the current problem of patient
non-compliance when treating OSA. These are not proposed to replace CPAP
altogether as the primary means of treating OSA, but rather to offer a more
accessible means of treating the disease for patients who do not adhere to CPAP
treatment. Another issue with CPAP is how our understanding of OSA has changed
from that as having a uniform fixed cause to that of a disease that has various
contributing factors, which presents the opportunity for more specific,
tailored therapies to be implemented. The key evidence for this lies in the
variability in the severity of these anatomical (upper airway impairment) and
non-anatomical (loop gain, arousal threshold) factors between patients (Eckert, 2018). Some patients may
suffer from impaired upper airway muscle dilator function but have normal loop
gain and arousal threshold while others have impairments in all three
phenotypes. This variability between patients in the severity of these factors
which are known to contribute to OSA should be cause for a re-evaluation of how
OSA is both assessed and treated. The aforementioned pharmacological therapies
could further improve the symptoms of OSA patients in combination with CPAP
therapy, as well as offer a means of treating patients who are non-compliant
with CPAP. This would of course necessitate a screening process by which these
anatomical and non-anatomical phenotypes can be assessed. The current screening
process for OSA consists of an overnight in-laboratory polysomnography (PSG) (Eckert, 2018), which primarily
measures the apnoea/hypopnoea index (AHI), the number of apneic events
per hour of sleep. Eckert proposes that the data collected from the PSG can be
used to determine the arousal threshold and loop gain of a patient. In my
opinion the assessment and treatment of OSA needs to be updated to reflect the
increased understanding of the various anatomical and non-anatomical factors
that are known to contribute to the severity of the disease.

Works Cited
Chan, E.,
Steenland, H., Liu, H. & Horner, R., 2006. Endogenous excitatory drive
modulating respiratory muscle activity across sleep–wake states. American
Journal of Respiratory and Critical Care, Volume 174, pp. 1264-1273.
Eckert, D. J., 2018. Phenotypic approaches to
obstructive sleep apnoea – New pathways for targeted therapy. Sleep
Medicine Reviews, Volume 37, pp. 1-137.
Eckert, D. J., Malhotra, A., Wellman, A. & White,
D. P., 2014. Trazodone Increases the Respiratory Arousal Threshold in Patients
with Obstructive Sleep Apnea and a Low Arousal Threshold. Sleep, 37(4),
pp. 811-819.
Eckert, D. J. et al., 2013. Defining Phenotypic Causes
of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets. American
Journal of Respitory and Critical Care Medicine, 188(8), pp. 996-1004.
Gray, E. L., McKenzie, D. K. & Eckert, D. J.,
2017. Obstructive Sleep Apnea without Obesity Is Common and Difficult to
Treat: Evidence for a Distinct Pathophysiological Phenotype. Journal of
Clinical Sleep Medicine, 15(1), pp. 81-88.
Punjabi, N. M., 2008. The Epidemiology of Adult
Obstructive Sleep Apnea. Proceedings of the american thoracic society, 5(2),
pp. 136-143.
Taranto-Montemurro, L. et al., 2015. Desipramine
Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during
Non-REM Sleep in Healthy Subjects. American Journal of Respiratory and
Critical Care Medicine, 194(7), pp. 878-885.
Torontali, Z., Grace, K., Horner, R. & Peever, J.,
2014. Cholinergic involvement in control of REM sleep paralysis. Journal of
Physiology, Volume 592, pp. 1425-1426.
Weaver, T. E. & Grunstein, R. R., 2008. Adherence
to Continuous Positive Airway Pressure Therapy The Challenge to Effective
Treatment. Proceedings of The American Thoracic Society, 5(2), pp.
173-178.
Wellman, A. et al., 2011. A method for measuring and
modeling the physiological traits causing obstructive sleep apnea. Journal
of Applied Physiology, 110(6), pp. 1627-1637.
Xie, C., Zhu, R., Tian, Y. & Wang, K., 2017.
Association of obstructive sleep apnoea with the risk of vascular outcomes and
all-cause mortality: a meta-analysis. BMJ Open, 7(12).
Younes, M., 2004. Role of Arousals in the Pathogenesis
of Obstructive Sleep Apnea. American Journal of Respiratory and Critical
Care Medicicne, Volume 169, pp. 623-633.
 

 

 

 

 

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