Respiratory effort and other pathophysiological mechanisms of obstructive sleep apnoea

Author: Laura Gell

Gell, Laura, 2019 Respiratory effort and other pathophysiological mechanisms of obstructive sleep apnoea, Flinders University, College of Science and Engineering

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Obstructive sleep apnoea (OSA) is a common respiratory disorder characterised by recurring upper airway collapse during sleep. OSA is associated with a number of serious negative effects on health and quality of life. Current main treatments include continuous positive airway pressure (CPAP), mandibular advancement devices, surgery and supine-avoidance, all of which focus on correcting anatomical abnormalities. However, low CPAP acceptance and variable efficacy with alternative treatments are such that the burden of untreated OSA is substantial. Furthermore, the pathogenesis of OSA is more complex than deficient anatomy alone, and a number of non-anatomical factors also contribute. All OSA patients can maintain airway patency during wake, but fail to successfully compensate for changes in muscle recruitment and respiratory drive following sleep onset. A fuller understanding of these fundamental compensatory mechanisms is needed to better guide potential therapeutic treatments for those for whom current options fail.

Respiratory effort plays a key role in modulating both upper airway and inspiratory pump muscle activity during sleep, and gradually augments following abrupt muscle relaxation at sleep onset. Brief cortical arousals from sleep to respiratory-related stimuli occur at a similar threshold of respiratory effort, suggesting that sensations arising from augmented inspiratory effort provide the primary stimulus for respiratory-related arousal. This may also explain the reduced OSA severity in deep sleep when effort increases and arousal frequency reduces. However, the more precise role of respiratory effort augmentation, either through central chemo-reflex drive, mechano-reflex responses or sleep stage related changes, in compensating for partial or complete airway collapse in OSA is not well understood. Nevertheless, respiratory effort and negative pressure effects are likely to be central to the sensitive balance between collapsing forces and muscle recruitment in the upper airway, which underpins pharyngeal patency.

The current ‘gold standard’ method of assessing respiratory effort in sleep is based on the inspiratory nadir in oesophageal pressure, usually recorded by a balloon catheter, to provide an estimate of pleural pressure swings. However, there are some limitations with this technique. Pressure signals are susceptible to significant cardiogenic artefact; the effect of occlusion on pressure swings is not well understood; and absolute values are difficult to interpret and compare between individuals due to inherent inter-individual differences in respiratory mechanics. Furthermore, the relationship between neural drive to breathe, inspiratory muscle recruitment and oesophageal pressure swings is complex, particularly in the presence of abrupt changes in upper airway resistance and lung volume in OSA, and these effects have not previously been adequately considered.

The aim of this thesis was to apply signal filtering and respiratory system mechanics principles to provide a more thorough understanding of the role of respiratory effort in OSA pathophysiology. This work uses theoretical consideration of respiratory mechanics to inform the development of a new method for assessing respiratory effort. Novel tools and algorithms were created to facilitate detailed, breath-by-breath and within-breath analysis of respiratory effort and muscle activity changes over the course of airway collapse and recovery in OSA. Results provided new insights into mechanisms underpinning airway obstruction onset and recovery.

Firstly, new filtering techniques were developed and tested to minimise cardiogenic artefact in both oesophageal pressure and diaphragmatic electromyography signals, allowing for more detailed comparisons of respiratory activity. Secondly, physiological recordings were used to investigate the effect of an externally applied occlusion on inspiratory oesophageal and airway pressure deflections in the context of classical respiratory system mechanics equations, suggesting that additional airway resistance would augment muscle loading and the resulting pressure deflections. This could be due to either distortion of the respiratory system altering elastance and resistance, intrinsic muscle compensation or reflex modulation of drive. The chest wall impedance term approaches zero with no flow and volume change, and should theoretically result in a more negative measured pressure for the same muscle pressure deflection. Oesophageal and epiglottic pressure swings were immediately more negative on the breath following occlusion onset, and these differences were remarkably well explained on the basis of increased ‘effective’ values of elastance and resistance in the classical respiratory equation of motion to account for chest wall effects. This approach enabled loading response to be separated from the underlying chemo-reflex drive component of oesophageal pressure. The combined effect was quantified, and then applied as a correction to oesophageal pressure to estimate total muscle pressure, a better measure of the underlying ventilatory drive, irrespective of occlusion.

A novel model of attempted ventilation was then derived from oesophageal pressure and the respiratory system equation of motion, accounting for occlusion effects by using the experimental findings of the previous study. By a rearrangement of the classical respiratory system equation of motion, the method very usefully predicts the flow that would have been expected to have been achieved from the driving pressure had airway patency been maintained. Respiratory effort can then be expressed in units of ventilation directly comparable to achieved ventilation, thus providing comprehensive new metrics of both effort and obstruction on a breath-by-breath basis.

This model was used to explore respiratory effort augmentation over periods of airway collapse and airflow recovery in OSA, and for examining relationships between changes in diaphragm and upper airway muscle activity with and without arousal. Results showed elevated ventilatory drive rapidly falling below baseline levels leading into airway obstruction, followed by augmented drive associated with subsequent airflow recovery, which was more exaggerated preceding arousal. Events with an arousal were associated with greater respiratory effort, a greater ventilatory overshoot, and increased risk of further collapse in the post-recovery period. This supports the hypothesis that increased drive at end-obstruction promotes arousal and an increased ventilatory response, which may leave the airway more susceptible to ongoing cyclical airway collapse.

It was observed that airflow recovery did not always correspond to the start of a respiratory effort, which led to a secondary study into the timing of airway re-opening, and the effort and muscle activity at the point of airflow restoration. This analysis showed that flow often resumed near the nadir of oesophageal pressure or into the subsequent passive recoil phase of the respiratory cycle, in association with reflex-like modulation of respiratory pattern generator timing itself. Thus inspiratory activity resumed with substantial changes in the respiratory duty cycle. This new observation has not been previously reported and warrants further studies to determine if it reflects a reflex contributing to airflow recovery, or occurs in response to flow restoration.

The work of this thesis provides important new insights into the understanding of respiratory effort in OSA. The demonstration that abrupt airway occlusion influences oesophageal and epiglottic pressure deflections has important implications for the assessment of respiratory effort in future physiological studies of OSA. The analytical tools developed from this work show major potential for providing important insights into the mechanisms of airway collapse, flow limitation and obstruction compensation. Application of these tools to other data sets, and across a wider sample of OSA patients and event types, would further enhance our understanding of the physiological mechanisms of OSA.

Keywords: Obstructive sleep apnoea, respiratory effort, ventilatory drive, oesophageal pressure, signal processing

Subject: Medical Science thesis

Thesis type: Doctor of Philosophy
Completed: 2019
School: College of Science and Engineering
Supervisor: Karen Reynolds