Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway
Introduction
The human pharynx during sleep exhibits substantial inspiratory narrowing as a result of the reduction in luminal pressure (Morrell and Badr, 1998). The upper airway is often modeled as a Starling resistor, which predicts that maximum flow is independent of inspiratory effort during flow limitation. That is, for increasing respiratory effort, flow should be constant (Gold and Schwartz, 1996). However, flow-limited breaths in obstructive sleep apnea (OSA) patients often exhibit negative effort dependence (NED), in which flow decreases as inspiratory effort increases. NED, as defined by the percentage reduction in flow from peak to mid-inspiration, can be marked (>50%) among OSA patients (Owens et al., 2014a). Using an experimental protocol in which the upper airway was passive (no muscle activity) we showed that all subjects had substantial NED (Owens et al., 2014b). During routine polysomnograms, however, NED can vary markedly between patients, with some exhibiting a very flat (no NED) Starling resistor-like flow limitation, whereas others demonstrate an almost 100% decrease in flow from early to mid-inspiration (Owens et al., 2014a). The mechanisms for this variability in NED are not known, but our prior work implies that muscle activity might be important.
Pharyngeal dilator muscle activity during sleep is determined by both central (i.e respiratory drive) and local (i.e. negative pressure reflex) inputs, and plays an essential role in the maintenance of pharyngeal patency (Eckert et al., 2013). During sleep, respiratory drive is primarily influenced by the chemoresponsiveness to PCO2 and PO2. When the central drive to the pharyngeal muscles was reduced via mechanical hyperventilation, we observed significant NED (Owens et al., 2014b). Such a finding suggests that the reduction of pharyngeal EMG activity may be responsible for the development of NED. However in our previous experiment, the relationship between the negative pressure reflex and the degree of NED was not assessed. The negative pressure reflex is induced by pharyngeal negative pressure and mediated by pharyngeal mechanoreceptors, resulting in phasic muscle activation, that mitigates the tendency for pharyngeal collapse during inspiration (Horner et al., 1991). However, pharyngeal muscle responsiveness to negative pressure varies considerably (Eckert et al., 2013). Therefore, we hypothesized that robust pharyngeal muscle responsiveness to negative pressure could potentially explain why some OSA patients do not exhibit major NED (i.e. fixed flow limitation—“Starling resistor like”), whereas ineffective muscle responsiveness could explain the appearance of NED. Recognizing the interaction of phasic muscle activation and NED is important for modeling/understanding the mechanisms of pharyngeal collapse in OSA. Specifically, we are interested in whether the pharynx is truly a Starling resistor, or rather if it simply appears to be like a Starling resistor because the phasic muscle activation offsets the underlying NED.
To test this hypothesis, topical pharyngeal anesthesia was used to blunt the negative pressure reflex and attenuate phasic muscle activation (Berry et al., 1997, Fogel et al., 2000, Horner et al., 1991). We then examined the relationship between muscle activation and NED before and after topical pharyngeal anesthesia.
Section snippets
Methods
Participants from both genders were recruited from the sleep laboratory at Brigham and Women's Hospital. All subjects had OSA and were being treated with CPAP. The age range was 21 to 70 years. Subjects were excluded if they had uncontrolled heart failure, diabetes or renal insufficiency, or if they were taking medications that could affect upper airway muscle function. The study was approved by the Hospital's Institutional Review Board and informed consent was obtained from each subject before
Results
Twenty-four subjects were enrolled in the study. Twelve subjects were excluded because they could either not fall asleep within 30 min after pharyngeal anesthesia administration (n = 9), or because the EMG signal quality was poor (n = 3). The characteristics of the 12 patients included in the analysis are presented in Table 1.
The average amount of lidocaine used was 3.5 ± 1.0 ml. The median number of breaths analyzed from each patient was 15.5 [13.3–25.8] and 14.0 [8.5 17.5] before and after
Discussion
The main finding of the present study was that upper airway anesthesia had little effect on the magnitude of NED observed. Our findings therefore suggest that the variability in NED found between OSA patients is not likely due to individual differences in inspiratory phasic pharyngeal muscle activation in response to negative luminal pressure.
Similar to previous studies, we were able to successfully attenuate inspiratory phasic EMGGG response to negative luminal pressure using pharyngeal
Research support
Dr. Genta was supported by Fapesp (Fundação de Amparo à Pesquisa do Estado de São Paulo). Dr. Edwards is supported by the National Health and Medical Research Council (NHMRC) of Australia's CJ Martin Overseas Biomedical Fellowship (1035115). Dr. Sands is supported by NHMRC Early Career Fellowship (1053201) and R.G. Menzies award. Dr. Wellman is supported by the NIH Grants R01 HL102321 and P01 NIHHL095491.
Disclosures
AW is a paid consultant for Philips Respironics and Galleon. AW's interests were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. DPW is Chief Scientific Officer for Apnicure and a consultant for Philips Respironics. DPW's interests were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. RLO is a paid consultant for
Acknowledgements
The authors would like to acknowledge Erik Smales, Lauren Hess and Alison Foster for technical assistance with the studies.
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