Accepted Manuscript. Mini-symposium. Sleep Disordered Breathing in Duchenne Muscular Dystrophy. Hemant Sawnani

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1 Accepted Manuscript Mini-symposium Sleep Disordered Breathing in Duchenne Muscular Dystrophy Hemant Sawnani PII: S (18) DOI: Reference: YPRRV 1277 To appear in: Paediatric Respiratory Reviews Please cite this article as: H. Sawnani, Sleep Disordered Breathing in Duchenne Muscular Dystrophy, Paediatric Respiratory Reviews (2018), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Sleep Disordered Breathing in Duchenne Muscular Dystrophy Corresponding author: Hemant Sawnani, MD Associate Professor, Division of Pediatric Pulmonology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH (USA) Text: 1930 words Figures: 5 References: 38 Key words: Duchenne; muscular dystrophy; sleep disordered breathing; neuromuscular disease Educational Aims: The reader will come to appreciate the: Variability of sleep disordered breathing presentation in Duchenne muscular dystrophy Pathophysiologic mechanisms of sleep disordered breathing in Duchenne muscular dystrophy Management and monitoring of sleep disordered breathing in Duchenne muscular dystrophy. Future Directions for Research There are indicators of impending sleep disordered breathing in boys with Duchenne muscular dystrophy. However, the accurate prediction of onset of early sleep disordered breathing and lack of clear relationship with evolving cardiomyopathy need to be explored further.

3 Summary Symptoms of sleep disordered breathing (SDB) in younger boys with DMD are often poorly perceived and/or articulated by the patients or their families. As a result it is the watchful eye of the care-provider that determines the need for early polysomnographic (PSG) assessments. The use of polysomnography without capnometry should be considered completely inadequate when it comes to diagnosis and management of SDB in these patients. The stabilization of gas exchange with non-invasive ventilation may be achieved by the use of pressure or volume support ventilation. Serial PSG assessments are recommended to assure optimal management as the patients clinical status evolves with disease progression and the emergence of additional morbidities such as cardiomyopathies, dysphagia, and chronic aspiration.

4 Duchenne Muscular Dystrophy (DMD) is characterized by relentless and progressive muscle weakness. The progressive weakness of the respiratory muscles causes impairment of cough and reduced secretion clearance, recurrent atelectasis and pneumonia, diurnal and finally chronic respiratory failure. While respiratory failure remains the leading cause of death in DMD(1), the time to death is variable. It has been suggested that mortality in stronger patients is often related to DMD-related cardiomyopathy, and attributed to respiratory failure in weaker patients (2). Earlier studies describing sleep disordered breathing in DMD focused on patients with more advanced states of weakness (3, 4). These data were published prior to the widespread use of systemic glucocorticoid (GC) treatment to delay progression (5-8). However, GC therapy can cause excessive weight gain and with progressive muscle weakness leads to progressive restrictive pulmonary defects and sleep disordered breathing (9). The changes in respiration during sleep in DMD are variable, insidious in onset, and a major cause of morbidity and mortality. With the progressive loss of inspiratory and expiratory muscle function there is loss of lung volume and reduced thoracic compliance, which can then increase work of breathing. This eventually leads to reduced alveolar ventilation. This initially presents while lying down sleeping at night, but in time will progress to affect awake, upright ventilation. For these reasons, having an accurate assessment of nocturnal ventilation is critical in managing patients with DMD. Respiratory abnormalities during sleep are poorly identified using sleep history, sleep diaries and assessing sleep hygiene. Consequently, polysomnography (PSG) is critical in the evaluation of sleep disordered breathing in patients with suspected hypoventilation. The American Academy of Sleep Medicine (AASM) supports routine polysomnography evaluation for patients with progressive neuromuscular diseases (10). Sleep Architecture in DMD Respiratory muscle weakness can lead to reduced total sleep time and efficiency (11, 12). These patients tend to exhibit marked sleep fragmentation with frequent nocturnal arousals (11, 12), increased light [stage 1] sleep (11) and reduced REM sleep (13). Because some subjects are most vulnerable to oxygen desaturation during REM sleep, its suppression may represent a compensatory mechanism. Lung function and sleep history have not been shown to be predictive of sleep disordered breathing in younger boys with DMD (9, 14). Therefore, PSG evaluation in boys with DMD is important for early identification of sleep disordered breathing, in particular hypoventilation, allowing for appropriate initiation with non-invasive ventilation. Respiratory events Sleep disordered breathing in DMD can present in various forms. In discussing these, it would be helpful to review briefly the physiologic changes anticipated with sleep onset. Under normal circumstances, sleep onset is associated with a mild elevation of 2-4 mmhg in carbon dioxide levels due to a reduction in tidal volume(15, 16), respiratory rate(17), and sensitivity of central chemoreceptors(15). Gould, et. al. showed that minute ventilation falls abruptly with sleep onset, and remains generally unchanged for

5 most of subsequent sleep(16). In addition, there is loss of the wakeful drive to breathe(18). It is important to understand that REM sleep is heterogeneously comprised of periods of phasic REMassociated bursts of rapid eye movements (phasic REM), and periods between these bursts of rapid eye movements (tonic REM). During phasic REM (periods of active rapid eye movements) sleep, breathing is irregular with periods of decreased rib cage motion and decreased tidal volume, but with increased respiratory rate and diaphragm activity(16). Upper airway resistance also increases abruptly following sleep onset. The change in ventilation is seen irrespective of whether a patient breathes through their native airway or via tracheostomy; therefore, the change in minute ventilation with sleep onset is not caused by a change in upper airway resistance(19). At the onset of sleep, patients with NMD have increased upper airway resistance due to an upper airway hypotonia and a lower resting lung volume (FRC) due to decreased intercostal muscle tone. The cephalad displacement of the diaphragm in the recumbent position amplifies these changes with further reduction in tidal volume and increased dead-space ventilation. These changes are magnified during rapid eye movement (REM) sleep when there is marked reduction in skeletal muscle tone, with the exception of the diaphragm and extra-ocular muscles. As a result, the diaphragm becomes the primary respiratory muscle during REM-sleep while the intercostal and accessory muscles maintain rib cage contributions to tidal volume during non-rem sleep. Therefore, chest wall excursion during REM-sleep is predominantly dependent on diaphragm function. This and the increased upper airways resistance causes greater thoracoabdominal asynchrony during REM sleep(20). These changes produce characteristic non-obstructive respiratory paradoxical breathing. Studies on younger populations of boys with DMD have shown that obstructive sleep apnea is the most common form of sleep disordered breathing (9, 14), occurring as early as 12 y of age. In the era with wide use of glucocorticoid therapy excessive weight gain is common, and it has been observed that the degree of sleep disordered breathing correlates linearly to body mass index(9). Often patients experienced mildly abnormal pulmonary function testing results, and neither they nor their parents/families reported snoring, daytime fatigue, non-restorative sleep. The obstructive apnea commonly manifests as severe REM-sleep related OSA(9, 21) with more profound desaturations and longer events observed in older patients with more severe restrictive lung defects(21). [Fig 1: Epoch of obstructive events in REM sleep] In children, alveolar hypoventilation is defined as more than 25% of total sleep time with arterial pco2 (or surrogate) greater than 50 mmhg(22). A significant limitation of this definition is that it does not take into account compensatory mechanisms to maintain normal CO2 levels awake (tachypnea) and asleep (tachypnea and sleep fragmentation). [Fig 2: Epoch of tachypnea awake; Fig 3: Epoch of tachypnea in REM sleep] Modifications to this definition have been proposed, such as 2%(23) or 5%(24) of total sleep time with transcutaneous CO2 levels greater than 50 mmhg. These are important considerations as the probability of daytime hypoventilation is very high within 1-2 years once a patient with neuromuscular disease has nocturnal hypoventilation(25). Hypoventilation can occur in combination with obstructive sleep apnea or in isolation. Although this has been well described in older subjects with DMD with advanced weakness, it has been reported in younger subjects (11-12 y) with mild restrictive pulmonary defects and respiratory muscle weakness(9). The primary mechanisms for hypoventilation include reduction of alveolar ventilation, blunted arousal thresholds and reduced respiratory muscle activity(26). The combinations of loss of upper airway muscle

6 tone, chest wall muscle hypotonia and diaphragm weakness may increase resistive loads, particularly during REM sleep, the state of maximal muscle hypotonia (27). Thus, elevations in carbon dioxide levels may occur in the absence of obvious apnea events. On polysomnographic tracings, these shallow breaths appear as non-obstructive reductions in airflow (hypopneas) and raise concerns of the possibility of respiratory muscle fatigue. [Fig 4A and 4B: Epoch of non-obstructive respiratory paradox in REM sleep] General Principles of Optimizing Ventilation Healthy, non-obese individuals normally demonstrate reductions in FRC during sleep(28), and this change is prominent during REM sleep(29). In addition, reduced caudal traction on the upper airway and decreased pharyngeal dilator activity cause upper airway hypotonia and predispose to obstructive events. In boys with DMD, the combination of muscle weakness, tendency to central obesity (related to glucocorticoid therapy), and REM-related hypotonia lead to reduced FRC and sleep disordered breathing. However, increasing the FRC during sleep(30-32) and anesthesia(33) can reduce airway collapsibility and sleep disordered breathing. While considering the treatment of sleep disordered breathing with non-invasive ventilation (NIV), bilevel pressure ventilation is the accepted standard of care. The lower end expiratory pressure provides the stenting effect on the upper airway and raises end-expiratory lung volume. The former effect stabilizes the upper airway while the latter helps improve oxygenation and ventilation by maintaining distal airway patency. The higher inspiratory pressure helps a patient breathe in more deeply and increases tidal volume, thereby improving ventilation. The difference between these two pressures, or the pressure support, is central to maintaining acceptable tidal volumes, regardless of the mode of ventilator support being offered. Although patients may experience no or little difficulty triggering a ventilator breath while awake or in non-rem sleep, the patient will begin to reveal greater difficulty to reliably trigger a breath in REM sleep and/or as the disease progresses. For this reason, it is important to add a back-up rate for the ventilator, set close to the anticipated physiologic rate for the patient. [Fig 5: Epoch of failure to trigger] More sophisticated ventilator modes allow setting of inspiratory time, cycle termination, trigger mode and sensitivity, and alarms for more accurate control of ventilation. A bilevel pressure titration study is the most precise way to identify the optimal ventilator settings for a patient. While identifying the optimal ventilator settings for each patient is very important, patient comfort will ultimately determine the success of NIV treatment, since well-conceived therapy that is not used is worthless. There are a variety of choices of interfaces available including nasal masks, oronasal masks, oral interfaces, and full face masks. The fit and comfort of the choice of mask is key to the patient s success in tolerating overnight ventilator support. If the mask is too tight it can cause discomfort and facial skin breakdown, but if it is too loose the air leak from the mask will be irritating to the patient and decrease the efficacy of the ventilation. Therefore, it is critical to have an experienced therapist properly identify and fit the NIV interface. Serial follow-up titration sleep studies of patients on ventilatory support may be needed as patients clinical conditions and needs change. Overnight oximetry is an inadequate manner to assess the

7 adequacy of ventilation in patients with neuromuscular weakness. Separate studies of a variety of ventilated neuromuscular patients have shown evidence of persistent nocturnal hypoventilation despite normal daytime capnometry and nighttime oximetry data (24, 34). Overnight oximetry studies are inexpensive and obtain than sleep studies, and when performed in the patient s home environment the patient may seep better giving a better representation of his/her sleep pattern. Home pulse oximetry cannot reassure that ventilation is adequate since only SpO 2 is being measured; however, there are recording units to measure both oxygenation and capnography. Lastly, normal gas exchange is not obligatorily associated with better sleep quality, the information of which can only be gleaned from a PSG. Summary Symptoms of SDB are challenging to elicit by history. Symptoms are often poorly perceived and articulated by children with NMD, and under-reported by parents (9, 35). This underscores the importance of an objective measure of sleep quality and sleep disordered breathing, and PSG evaluations are the gold standard test for this. The link between lung function and hypoventilation and the correlation between symptoms and hypoventilation are dubious. Should there be any concern about progression of disease, and certainly after loss of ambulation, PSG evaluation should be performed to assess the stability of ventilation. Such testing allows for the early identification and diagnosis of sleep disordered breathing, allowing for the timely initiation of respiratory support. Sleep-related respiratory disturbances can present as obstructive or central events, non-apneic hypoxemia, hypoventilation, and any combination of these. PSGs performed without capnometry are woefully inadequate in the diagnosis and management of sleep disordered breathing of neuromuscular origin. Optimal titration of pressures is recommended to be performed using PSG. Such a study is not only limited to identifying appropriate ventilating pressures, but also includes identifying appropriately fitting masks, correcting related air leaks - all issues that could adversely affect adherence to the prescribed ventilation strategy. Besides correcting gas-exchange abnormalities and improving sleep quality, the use of such non-invasive ventilation has been shown to improve survival and quality of life of adults and children with neuromuscular diseases (36-38).

8 Legends: Fig 1: A 1-minute screenshot of obstructive events in supine REM sleep. Note the tendency of events to occur in tandem with phasic REM sleep. Fig 2: A 1-minute screenshot of tachypnea while awake in a 17-year-old boy with DMD. Note the respiratory paradox while awake. Fig 3: A 1-min screenshot of an adolescent with DMD manifesting tachypnea in REM sleep. There respiratory paradox often noted during phasic REM sleep. Fig 4A: A 5-minute screenshot of non-obstructive respiratory paradox without alveolar hypoventilation in Stage N2. Fig 4B: A 90-second screenshot of the same patient showing non-obstructive respiratory paradox with alveolar hypoventilation and hypoxemia in REM sleep. The marked reduction of intercostal activity with this event is easily observed. Fig 4C: A 90-second screenshot of the same patient showing non-obstructive respiratory paradox with alveolar hypoventilation and hypoxemia in REM sleep. Figures 4A, 4B and 4C are of sequential epochs. Fig 5A: A 1-minute screenshot of non-invasive titration with the patient s respiratory rate almost twice that of the ventilator rate, revealing asynchrony of support. Numerous causes exist for failure to trigger, and these may be related to leak, ventilator sensitivity and extreme weakness. All of these need to be addressed, if possible, during the titration study. Such a patient would still likely experience respiratory fatigue upon waking. Fig 5B: A 90-second screenshot of non-invasive titration with the patient s respiratory rate almost twice that of the ventilator rate, revealing asynchrony of support. The machine had been placed in Timed (T) mode as a technical error.

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