Lisa M. Campana

Neurogenic Changes in the Upper Airway of Patients with Obstructive Sleep Apnea

RATIONALE Controversy persists regarding the presence and importance of hypoglossal nerve dysfunction in obstructive sleep apnea (OSA). OBJECTIVES We assessed quantitative parameters related to motor unit potential (MUP) morphology derived from electromyographic (EMG) signals in patients with OSA versus control subjects and hypothesized that signs of neurogenic remodeling would be present in the patients with OSA. METHODS Participants underwent diagnostic sleep studies to obtain apnea-hypopnea indices. Muscle activity was detected with 50-mm concentric needle electrodes. The concentric needle was positioned at more than 10 independent sites per subject, after the local anatomy of the upper airway musculature was examined by ultrasonography. All activity was quantified with subjects awake, during supine eupneic breathing while wearing a nasal mask connected to a pneumotachograph. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which extracted motor unit potential trains (MUPTs) contributed by individual motor units from the composite EMG signals. Quantitative measurements of MUP templates, including duration, peak-to-peak amplitude, area, area-to-amplitude ratio, and size index, were compared between the untreated patients with OSA and healthy control subjects. MEASUREMENTS AND MAIN RESULTS A total of 1,655 MUPTs from patients with OSA (n = 17; AHI, 55 ± 6/h) and control subjects (n = 14; AHI, 4 ± 1/h) were extracted from the genioglossus muscle EMG signals. MUP peak-to-peak amplitudes in the patients with OSA were not different compared with the control subjects (397.5 ± 9.0 vs. 382.5 ± 10.0 μV). However, the MUPs of the patients with OSA were longer in duration (11.5 ± 0.1 vs. 10.3 ± 0.1 ms; P < 0.001) and had a larger size index (4.09 ± 0.02 vs. 3.92 ± 0.02; P < 0.001) compared with control subjects. CONCLUSIONS These results confirm and quantify the extent and existence of structural neural remodeling in OSA.

Acetazolamide Attenuates the Ventilatory Response to Arousal in Patients with Obstructive Sleep Apnea

STUDY OBJECTIVES The magnitude of the post-apnea/hypopnea ventilatory overshoot following arousal may perpetuate subsequent respiratory events in obstructive sleep apnea (OSA) patients, potentially contributing to the disorders severity. As acetazolamide can reduce apnea severity in some patients, we examined the effect of acetazolamide on the ventilatory response to spontaneous arousals in CPAP-treated OSA patients. DESIGN We assessed the ventilatory response to arousal in OSA patients on therapeutic CPAP before and after administration of acetazolamide for 7 days. SETTING Sleep research laboratory. PARTICIPANTS 12 (7M/5F) CPAP-treated OSA patients. INTERVENTIONS Sustained-release acetazolamide 500 mg by mouth twice daily for one week. MEASUREMENTS AND RESULTS A blinded investigator identified spontaneous arousals (3-15 s) during NREM sleep. Breath-by-breath measurements of minute ventilation, end-tidal CO(2), tidal volume, expiratory/inspiratory-time, and total breath duration were determined (4-s intervals) 32 s prior and 60 s following each arousal. Acetazolamide significantly increased resting ventilation (7.3 ± 0.2 L/min versus 8.2 ± 0.4 L/min; P < 0.05) and attenuated the percent increase in ventilation following arousal by ~2.5 fold (122.0% ± 4.4% versus 108.7% ± 3.5% pre-arousal level; P < 0.05). There was a positive correlation between the mean increase in ventilatory response to arousal and mean AHI (r(2) = 0.44, P = 0.01). However, absolute peak levels of ventilation following arousal remained unchanged between conditions (8.8 ± 0.4 L/min versus 8.9 ± 0.1 L/min). CONCLUSIONS Acetazolamide substantially attenuates the increase in ventilation following spontaneous arousal from sleep in OSA patients. This study suggests an additional mechanism by which acetazolamide may contribute to the improvement in ventilatory instability and OSA severity. The data also provide support for reinforcing the importance of ventilatory control in OSA pathogenesis.

Sitting and supine esophageal pressures in overweight and obese subjects.

Esophageal pressure (PEs) can be used to approximate pleural pressure (Ppl) and might be clinically useful, particularly in the obese e.g., to guide mechanical ventilator settings in critical illness. However, mediastinal artifact (the difference between true Ppl and PEs) may limit acceptance of the measurement, and reproducibility of PEs measurements remains unknown. Therefore, we aimed to assess the effect of body posture on PEs in a cohort of obese, but healthy subjects, some of whom had multiple measurements, to address the clinical robustness of esophageal manometry. Twenty‐five overweight and obese subjects (BMI > 25 kg/m2) and 11 control lean subjects (BMI < 25 kg/m2) underwent esophageal manometry with pressures measured seated and supine. Twenty overweight and obese subjects had measurements repeated after ∼1 to 2 weeks. Anthropometric data and sitting and supine spirometry were recorded. The average end‐expiratory PEs sitting and supine were greater in the overweight and obese group than the lean group (sitting −0.1 ± 2.1 vs. −3.3 ± 1.2 cmH2O, supine 9.3 ± 3.3 vs. 6.9 ± 2.8 cmH2O, respectively). The mean differences between repeated measurements were small (−0.3 ± 1.7 cmH2O sitting and −0.1 ± 1.5 cmH2O supine). PEs correlated with a number of anthropometric and spirometric variables. In conclusion, PEs are slightly greater in overweight and obese subjects than lean subjects; but changes with position are similar in both groups. These data indicate that mediastinal weight and postural effects on PEs are within a clinically acceptable range, and suggest that esophageal manometry can be used to inform clinical decision making across wide range of body types.

Phase-rectified signal averaging as a sensitive index of autonomic changes with aging

Standard heart rate variability (HRV) techniques have been questioned in the sleep and autonomic fields as imprecise measures of sympathetic and parasympathetic activity. A new technique has emerged, known as phase-rectified signal averaging (PRSA). PRSA is used to quantify the quasi-periodic accelerations and decelerations in short-term heart rate, an effect that is normally masked by artifacts and noise. When applied to a signal of peak-to-peak (RR) time intervals, these quasiperiodicities can be used to estimate overall vagal activity, quantified as deceleration capacity (DC) and acceleration capacity (AC). We applied the PRSA analysis to a healthy cohort (ages 21-60 yr) enrolled in a clinical sleep trial, in which ECG data during wakefulness and sleep were available. We found that DC and AC were significantly attenuated with increasing age: a 0.27 ms/yr decrease in DC and a 0.29 ms/yr increase in AC (P<0.001). However, even in the older subjects, DC values were higher then previously found in people post-myocardial infarction. We also found a drop in percentage of normal-to-normal intervals where the current interval deviated>50 ms from the previous interval with age, with a decrease of 0.84%/yr. We did not find any differences between younger and older subjects with traditional HRV techniques, such as low-frequency or high-frequency power. Overall, the study provides normative PRSA data and suggests that PRSA is more sensitive than other HRV measurements. We propose that the decrease in DC and AC may be a sensitive marker for autonomic changes with aging. Further work will be required to determine whether the observed changes predict poorer cardiac health prognosis.

A pilot study investigating the effects of continuous positive airway pressure treatment and weight-loss surgery on autonomic activity in obese obstructive sleep apnea patients.

BACKGROUND We have previously demonstrated that severity of obstructive sleep apnea (OSA) as measured by the apnea-hypopnea index (AHI) is a significant independent predictor of readily-computed time-domain metrics of short-term heart rate variability (HRV). METHODS We aimed to assess time-domain HRV measured over 5-min while awake in a trial of obese subjects undergoing one of two OSA therapies: weight-loss surgery (n=12, 2 males, median and interquartile range (IQR) for BMI 43.7 [42.0, 51.4] kg/m2, and AHI 18.1 [16.3, 67.5] events/h) or continuous positive airway pressure (CPAP) (n=15, 11 males, median BMI 33.8 [31.3, 37.9] kg/m2, and AHI 36.5 [24.7, 77.3] events/h). Polysomnography was followed by electrocardiography during wakefulness; measurements were repeated at 6 and 12-18 months post-intervention. RESULTS Despite similar measurements at baseline, subjects who underwent surgery exhibited greater improvement in short-term HRV than those who underwent CPAP (p=0.04). CONCLUSIONS Our data suggest a possible divergence in autonomic function between the effects of weight loss resulting from bariatric surgery, and the amelioration of obstructive respiratory events resulting from CPAP treatment. Randomized studies are necessary before clinical recommendations can be made.

The effect of lung stretch during sleep on airway mechanics in overweight and obese asthma

Both obesity and sleep reduce lung volume and limit deep breaths, possibly contributing to asthma. We hypothesize that increasing lung volume dynamically during sleep would reduce airway resistance in asthma. Asthma (n=10) and control (n=10) subjects were studied during sleep at baseline and with increased lung volume via bi-level positive airway pressure (BPAP). Using forced oscillations, respiratory system resistance (R(rs)) and reactance (X(rs)) were measured during sleep and R(rs) was partitioned to upper and lower airway resistance (R(up), R(low)) using an epiglottic pressure catheter. R(rs) and R(up) increased with sleep (p<0.01) and X(rs) was decreased in REM (p=0.02) as compared to wake. R(rs), R(up), and R(low), were larger (p<0.01) and X(rs) was decreased (p<0.02) in asthma. On BPAP, R(rs) and R(up) were decreased (p<0.001) and X(rs) increased (p<0.01), but R(low) was unchanged. High R(up) was observed in asthma, which reduced with BPAP. We conclude that the upper airway is a major component of R(rs) and larger lung volume changes may be required to alter R(low).

A Possible Method to Predict Response to Non-Pharmacological Insomnia Therapy

STUDY OBJECTIVES To determine if electrocardiographic parameters are predictive of response to non-pharmacological insomnia therapy. DESIGN Secondary analysis of heart rate parameters from a double blind, randomized, sham-controlled trial at multiple study sites. SETTING Six sites in the United States were used for the data collection. PARTICIPANTS One hundred ninety-eight healthy subjects with no sleep disorders. INTERVENTIONS Subjects were studied on 2 consecutive nights, a baseline night and a therapy night. On the therapy night, subjects were phase advanced 4 h and randomized to receive either sham or vestibular stimulation, an experimental therapy for insomnia. MEASUREMENTS AND RESULTS ECG data were recorded and analyzed for the 5-min periods preceding and following sleep onset. Analyses were conducted on those who did and did not respond to therapy, as defined by latency from bedtime to persistent sleep (LPS). Responders to therapy were found to have higher low-frequency (LF) power at baseline during wakefulness than non-responders, and responders had higher high-frequency (HF) power during therapy than non-responders on therapy. Furthermore, responders > 35 y had elevated LF power at baseline than non-responders > 35 y (p < 0.05). No differences were seen in the sham group in identical analyses, ruling out a nonspecific effect of sleep onset. CONCLUSIONS Heart rate variability analyses indicate that differences exist between those who respond to insomnia therapy and those that do not, particularly in an older subset of subjects. Further research into the use of ECG and other physiological parameters to stratify response to therapeutic interventions is warranted.