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1.  Influence of wakefulness on pharyngeal airway muscle activity 
Thorax  2007;62(9):799-805.
Whether loss of wakefulness itself can influence pharyngeal dilator muscle activity and responsiveness is currently unknown. A study was therefore undertaken to assess the isolated impact of sleep on upper airway muscle activity after minimising respiratory/mechanical inputs.
Ten healthy subjects were studied. Genioglossus (GG), tensor palatini (TP) and diaphragm (DIA) electromyography (EMG), ventilation and sleep‐wake status were recorded. Non‐invasive positive pressure ventilation was applied. Expiratory pressure was adjusted to yield the lowest GGEMG, thereby minimising airway negative pressure (mechanoreceptor) effects. Inspiratory pressure, respiratory rate and inspiratory time were adjusted until the subjects ceased spontaneous ventilation, thereby minimising central respiratory input. Muscle activity during wakefulness, wake‐sleep transitions, stable non‐rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep were evaluated in the supine position.
In transitions from wakefulness to sleep, significant decrements were observed in both mean GGEMG and TPEMG (1.6 (0.5)% to 1.3 (0.4)% of maximal GGEMG; 4.3 (2.3)% to 3.7 (2.1)% of maximal TPEMG). Compared with sleep onset, the activity of TP during stable NREM sleep and REM sleep was further decreased (3.7 (2.1)% vs 3.0 (2.0)% vs 3.0 (2.0)% of maximal EMG). However, GGEMG was only further reduced during REM sleep (1.3 (0.4)% vs 1.0 (0.3)% vs 1.1 (0.4)% of maximal EMG).
This study suggests that wakefulness per se, independent of respiratory/mechanical stimuli, can influence pharyngeal dilator muscle activity.
PMCID: PMC2117303  PMID: 17389755
2.  Genioglossal Muscle Response to CO2 Stimulation During NREM Sleep 
Sleep  2006;29(4):470-477.
Study Objectives
The objective was to evaluate the responsiveness of upper airway muscles to hypercapnia with and without intrapharyngeal negative pressure during non-rapid eye movement (NREM) sleep and wakefulness.
We assessed the genioglossal muscle response to CO2 off and on continuous positive airway pressure (CPAP) (to attenuate negative pressure) during stable NREM sleep and wakefulness in the supine position.
Laboratory of the Sleep Medicine Division, Brigham and Women’s Hospital.
Patients or Participants
Eleven normal healthy subjects.
During wakefulness and NREM sleep, we measured genioglossal electromyography (EMG) on and off CPAP at the normal eupneic level and at levels 5 and 10 mm Hg above the awake eupneic level.
Measurements and Results
We observed that CO2 could increase upper- airway muscle activity during NREM sleep and wakefulness in the supine position with and without intrapharyngeal negative pressure. The application of nasal CPAP significantly decreased genioglossal EMG at all 3 levels of PETCO2 during NREM sleep (13.0 ± 4.9% vs. 4.6 ± 1.6% of maximal EMG, 14.6 ± 5.6% vs. 7.1 ± 2.3% of maximal EMG, and 17.3 ± 6.3% vs. 10.2 ± 3.1% of maximal EMG, respectively). However, the absence of negative pressure in the upper airway did not significantly affect the slope of the pharyngeal airway dilator muscle response to hypercapnia during NREM sleep (0.72 ± 0.30% vs. 0.79 ± 0.27% of maximal EMG per mm Hg PCO2 , respectively, off and on CPAP).
We conclude that both chemoreceptive and negative pressure reflex inputs to this upper airway dilator muscle are still active during stable NREM sleep.
PMCID: PMC3500386  PMID: 16676780
Genioglossus; hypercapnia; sleep; upper airway; pharynx; continuous positive airway pressure; respiration
3.  Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans 
Thorax  2007;62(10):861-867.
Most patients with obstructive sleep apnoea (OSA) can restore airflow after an obstructive respiratory event without arousal at least some of the time. The mechanisms that enable this ventilatory recovery are unclear but probably include increased upper airway dilator muscle activity and/or changes in respiratory timing. The aims of this study were to compare the ability to recover ventilation and the mechanisms of compensation following a sudden reduction of continuous positive airway pressure (CPAP) in subjects with and without OSA.
Ten obese patients with OSA (mean (SD) apnoea‐hypopnoea index 62.6 (12.4) events/h) and 15 healthy non‐obese non‐snorers were instrumented with intramuscular genioglossus electrodes and a mask/pneumotachograph which was connected to a modified CPAP device that could deliver either continuous positive or negative pressure. During stable non‐rapid eye movement sleep the CPAP was repeatedly reduced 2–10 cm H2O below the level required to eliminate flow limitation and was held at this level for 5 min or until arousal from sleep occurred.
During reduced CPAP the increases in genioglossus activity (311.5 (49.4)% of baseline in subjects with OSA and 315.4 (76.2)% of baseline in non‐snorers, p = 0.9) and duty cycle (123.8 (3.9)% of baseline in subjects with OSA and 118.2 (2.8)% of baseline in non‐snorers, p = 0.4) were similar in both groups, yet patients with OSA could restore ventilation without cortical arousal less often than non‐snorers (54.1% vs 65.7% of pressure drops, p = 0.04). When ventilatory recovery did not occur, genioglossus muscle and respiratory timing changes still occurred but these did not yield adequate pharyngeal patency/ventilation.
Compensatory mechanisms (increased genioglossus muscle activity and/or duty cycle) often restore ventilation during sleep but may be less effective in obese patients with OSA than in non‐snorers.
PMCID: PMC2094262  PMID: 17412778
4.  Associated bone mineral density and obstructive sleep apnea in chronic obstructive pulmonary disease 
Osteoporosis is an important issue for patients with chronic obstructive pulmonary disease (COPD). Worse systemic inflammation and reduced exercise capacity have been reported in COPD patients with obstructive sleep apnea (OSA), implying that OSA may be an independent factor for osteoporosis in COPD patients.
A total of 66 patients with bone mineral density (BMD) and polysomnography results from a previous COPD cohort (January 2008 to January 2013) were retrospectively enrolled. Clinical characteristics such as medication, pulmonary function, BMD, and results of polysomnography were analyzed.
The BMD in those with OSA was significantly lower than in those without OSA (−1.99±1.63 versus −1.27±1.14, P=0.045). In univariate analysis, body mass index, forced expiratory volume in 1 second, percentage of predicted value, incremental shuttle walk test, apnea–hypopnea index, and oxygen desaturation index (ODI) were significantly associated with BMD. After multivariate linear regression analysis, the ODI was still an independent factor for BMD. In addition, smaller total lung capacity is significantly associated with higher ODI and lower BMD, which implies that lower BMD might cause severer OSA via decreased total lung capacity.
OSA may be an independent factor for BMD in patients with COPD, which implies a possible vicious cycle takes place in these patients.
PMCID: PMC4321657
chronic obstructive pulmonary disease; osteoporosis; total lung capacity
5.  Comparative Effects of Snoring Sound between Two Minimally Invasive Surgeries in the Treatment of Snoring: A Randomized Controlled Trial 
PLoS ONE  2014;9(5):e97186.
Minimally invasive surgeries of the soft palate have emerged as a less-invasive treatment for habitual snoring. To date, there is only limited information available comparing the effects of snoring sound between different minimally invasive surgeries in the treatment of habitual snoring.
To compare the efficacy of palatal implant and radiofrequency surgery, in the reduction of snoring through subjective evaluation of snoring and objective snoring sound analysis.
Patients and Method
Thirty patients with habitual snoring due to palatal obstruction (apnea-hypopnea index ≤15, body max index ≤30) were prospectively enrolled and randomized to undergo a single session of palatal implant or temperature-controlled radiofrequency surgery of the soft palate under local anesthesia. Snoring was primarily evaluated by the patient with a 10 cm visual analogue scale (VAS) at baseline and at a 3-month follow-up visit and the change in VAS was the primary outcome. Moreover, life qualities, measured by snore outcomes survey, and full-night snoring sounds, analyzed by a sound analytic program (Snore Map), were also investigated at the same time.
Twenty-eight patients completed the study; 14 received palatal implant surgery and 14 underwent radiofrequency surgery. The VAS and snore outcomes survey scores were significantly improved in both groups. However, the good response (postoperative VAS ≤3 or postoperative VAS ≤5 plus snore outcomes survey score ≥60) rate of the palatal implant group was significantly higher than that of the radiofrequency group (79% vs. 29%, P = 0.021). The maximal loudness of low-frequency (40–300 Hz) snores was reduced significantly in the palatal implant group. In addition, the snoring index was significantly reduced in the radiofrequency group.
Both palatal implants and a single-stage radiofrequency surgery improve subjective snoring outcomes, but palatal implants have a greater effect on most measures of subjective and objective snoring. Multi-stage radiofrequency surgery was not tested.
Trial Registration NCT01955083
PMCID: PMC4016275  PMID: 24816691
6.  Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice 
Obstructive sleep apnoea (OSA) has recently been identified as a possible aetiology for chronic cough. The aim of this study was to compare the incidence of chronic cough between patients with and without OSA and the impact of continuous positive airway pressure (CPAP) treatment in resolving chronic cough.
Patients referred to the sleep laboratory from January 2012 to June 2012 were retrospectively enrolled. Clinical data, treatment course and resolution of chronic cough were analysed. Specifically, gastro-oesophageal reflux (GERD), upper airway cough syndrome, asthma, apnoea-hypopnoea index and the impact of CPAP treatment on chronic cough were assessed.
A total of 131 patients were reviewed. The incidence of chronic cough in the OSA group was significantly higher than the non-OSA group (39/99 (39.4%) vs. 4/32 (12.5%), p = 0.005). Both GERD and apnoea-hypopnoea index were significantly associated with chronic cough in univariate analysis. After multivariate logistic regression, GERD was the only independent factor for chronic cough. Moreover, the resolution of chronic cough was more significant in the OSA patients with CPAP treatment compared with those not receiving CPAP treatment (12/18 (66.7%) vs. 2/21 (9.5%), p = 0.010).
The incidence of chronic cough was significantly higher in the OSA patients. In addition, CPAP treatment significantly improved chronic cough. Therefore, OSA may be a contributory factor to chronic cough.
PMCID: PMC4176501  PMID: 24188336
Chronic cough; Obstructive sleep apnoea; Continuous positive airway pressure
7.  Nocturnal CPAP improves walking capacity in COPD patients with obstructive sleep apnoea 
Respiratory Research  2013;14(1):66.
Exercise limitation is an important issue in patients with chronic obstructive pulmonary disease (COPD), and it often co-exists with obstructive sleep apnoea (overlap syndrome). This study examined the effects of nocturnal continuous positive airway pressure (CPAP) treatment on walking capacity in COPD patients with or without obstructive sleep apnoea.
Forty-four stable moderate-to-severe COPD patients were recruited and completed this study. They all underwent polysomnography, CPAP titration, accommodation, and treatment with adequate pressure. The incremental shuttle walking test was used to measure walking capacity at baseline and after two nights of CPAP treatment. Urinary catecholamine and heart rate variability were measured before and after CPAP treatment.
After two nights of CPAP treatment, the apnoea-hypopnoea index and oxygen desaturation index significantly improved in both overlap syndrome and COPD patients, however these changes were significantly greater in the overlap syndrome than in the COPD group. Sleep architecture and autonomic dysfunction significantly improved in the overlap syndrome group but not in the COPD group. CPAP treatment was associated with an increased walking capacity from baseline from 226.4 ± 95.3 m to 288.6 ± 94.6 m (P < 0.05), and decreased urinary catecholamine levels, pre-exercise heart rate, oxygenation, and Borg scale in the overlap syndrome group. An improvement in the apnoea-hypopnoea index was an independent factor associated with the increase in walking distance (r = 0.564).
Nocturnal CPAP may improve walking capacity in COPD patients with overlap syndrome.
Trial registration
PMCID: PMC3689615  PMID: 23782492
Chronic obstructive pulmonary disease; Obstructive sleep apnoea; Walking capacity; Autonomic dysfunction; Continuous positive airway pressure
8.  The Potential Regimen of Target-Controlled Infusion of Propofol in Flexible Bronchoscopy Sedation: A Randomized Controlled Trial 
PLoS ONE  2013;8(4):e62744.
Target-controlled infusion (TCI) provides precise pharmacokinetic control of propofol concentration in the effect-site (Ce), eg. brain. This pilot study aims to evaluate the feasibility and optimal TCI regimen for flexible bronchoscopy (FB) sedation.
After alfentanil bolus, initial induction Ce of propofol was targeted at 2 μg/ml. Patients were randomized into three titration groups (i.e., by 0.5, 0.2 and 0.1 μg/ml, respectively) to maintain stable sedation levels and vital signs. Adverse events, frequency of adjustments, drug doses, and induction and recovery times were recorded.
The study was closed early due to significantly severe hypoxemia events (oxyhemoglobin saturation <70%) in the group titrated at 0.5 μg/ml. Forty-nine, 49 and 46 patients were enrolled into the 3 respective groups before study closure. The proportion of patients with hypoxemia events differed significantly between groups (67.3 vs. 46.9 vs. 41.3%, p = 0.027). Hypotension events, induction and recovery time and propofol doses were not different. The Ce of induction differed significantly between groups (2.4±0.5 vs. 2.1±0.4 vs. 2.1±0.3 μg/ml, p = 0.005) and the Ce of procedures was higher at 0.5 μg/ml titration (2.4±0.5 vs. 2.1±0.4 vs. 2.2±0.3 μg/ml, p = 0.006). The adjustment frequency tended to be higher for titration at 0.1 μg/ml but was not statistically significant (2 (0∼6) vs. 3 (0∼6) vs. 3 (0∼11)). Subgroup analysis revealed 14% of all patients required no further adjustment during the whole sedation. Comparing patients requiring at least one adjustment with those who did not, they were observed to have a shorter induction time (87.6±34.9 vs. 226.9±147.9 sec, p<0.001), a smaller induction dose and Ce (32.5±4.1 vs. 56.8±22.7 mg, p<0.001; 1.76±0.17 vs. 2.28 ±0.41, p<0.001, respectively), and less hypoxemia and hypotension (15.8 vs.56.9%, p = 0.001; 0 vs. 24.1%, p = 0.008, respectively).
Titration at 0.5 μg/ml is risky for FB sedation. A subgroup of patients required no more TCI adjustment with fewer complications. Further studies are warranted to determine the optimal regimen of TCI for FB sedation.
Trial Registration NCT01101477
PMCID: PMC3634750  PMID: 23638141
9.  Energy Types of Snoring Sounds in Patients with Obstructive Sleep Apnea Syndrome: A Preliminary Observation 
PLoS ONE  2012;7(12):e53481.
Annoying snore is the principle symptom and problem in obstructive sleep apnea syndrome (OSAS). However, investigation has been hampered by the complex snoring sound analyses.
This study was aimed to investigate the energy types of the full-night snoring sounds in patients with OSAS.
Patients and Method
Twenty male OSAS patients underwent snoring sound recording throughout 6 hours of in-lab overnight polysomnogragphy. Snoring sounds were processed and analyzed by a new sound analytic program, named as Snore Map®. We transformed the 6-hour snoring sound power spectra into the energy spectrum and classified it as snore map type 1 (monosyllabic low-frequency snore), type 2 (duplex low-&mid-frequency snore), type 3 (duplex low- & high-frequency snore), and type 4 (triplex low-, mid-, & high-frequency snore). The interrator and test-retest reliabilities of snore map typing were assessed. The snore map types and their associations among demographic data, subjective snoring questionnaires, and polysomnographic parameters were explored.
The interrator reliability of snore map typing were almost perfect (κ = 0.87) and the test-retest reliability was high (r = 0.71). The snore map type was proportional to the body mass index (r = 0.63, P = 0.003) and neck circumference (r = 0.52, P = 0.018). Snore map types were unrelated to subjective snoring questionnaire scores (All P>0.05). After adjustment for body mass index and neck circumference, snore map type 3–4 was significantly associated with severity of OSAS (r = 0.52, P = 0.026).
Snore map typing of a full-night energy spectrum is feasible and reliable. The presence of a higher snore map type is a warning sign of severe OSAS and indicated priority OSAS management. Future studies are warranted to evaluate whether snore map type can be used to discriminate OSAS from primary snoring and whether it is affected by OSAS management.
PMCID: PMC3534069  PMID: 23300931
10.  Feasibility of Bispectral Index-Guided Propofol Infusion for Flexible Bronchoscopy Sedation: A Randomized Controlled Trial 
PLoS ONE  2011;6(11):e27769.
There are safety issues associated with propofol use for flexible bronchoscopy (FB). The bispectral index (BIS) correlates well with the level of consciousness. The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation, benefiting the patients and bronchoscopists.
After administering alfentanil bolus, 500 patients were randomized to either propofol infusion titrated to a BIS level of 65-75 (study group) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation. The primary endpoint was safety, while the secondary endpoints were recovery time, patient tolerance, and cooperation.
The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups (study vs. control groups: 39.9% vs. 35.7%, p = 0.340; 7.4% vs. 4.4%, p = 0.159, respectively). The mean lowest blood pressure was lower in the study group. Logistic regression revealed male gender, higher American Society of Anesthesiologists physical status, and electrocautery were associated with hypoxemia, whereas lower propofol dose for induction was associated with hypotension in the study group. The study group had better global tolerance (p<0.001), less procedural interference by movement or cough (13.6% vs. 36.1%, p<0.001; 30.0% vs. 44.2%, p = 0.001, respectively), and shorter time to orientation and ambulation (11.7±10.2 min vs. 29.7±26.8 min, p<0.001; 30.0±18.2 min vs. 55.7±40.6 min, p<0.001, respectively) compared to the control group.
BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance, with fast recovery and less procedure interference.
Trial Registration
ClinicalTrials. gov NCT00789815
PMCID: PMC3223212  PMID: 22132138
11.  Diagnostic Value of EBUS-TBNA for Lung Cancer with Non-Enlarged Lymph Nodes: A Study in a Tuberculosis-Endemic Country 
PLoS ONE  2011;6(2):e16877.
In tuberculosis (TB)-endemic areas, contrast-enhanced computed tomography (CT) and positron emission tomography (PET) findings of lung cancer patients with non-enlarged lymph nodes are frequently discrepant. Endobronchial ultrasound-guided transbronchial aspiration (EBUS-TBNA) enables real-time nodal sampling, and thereby improves nodal diagnosis accuracy. This study aimed to compare the accuracy of nodal diagnosis by using EBUS-TBNA, and PET.
We studied 43 lung cancer patients with CT-defined non-enlarged mediastinal and hilar lymph nodes and examined 78 lymph nodes using EBUS-TBNA.
The sensitivity, specificity, positive predictive value, and negative predictive value of EBUS-TBNA were 80.6%, 100%, 100%, and 85.7%, respectively. PET had low specificity (18.9%) and a low positive predictive value (44.4%). The diagnostic accuracy of EBUS-TBNA was higher than that of PET (91% vs. 47.4%; p<0.001). Compared to CT-based nodal assessment, PET yielded a positive diagnostic impact in 36.9% nodes, a negative diagnostic impact in 46.2% nodes, and no diagnostic impact in 16.9% nodes. Patients with lymph nodes showing negative PET diagnostic impact had a high incidence of previous pulmonary TB. Multivariate analysis indicated that detection of hilar nodes on PET was an independent predictor of negative diagnostic impact of PET.
In a TB-endemic area with a condition of CT-defined non-enlarged lymph node, the negative diagnostic impact of PET limits its clinical usefulness for nodal staging; therefore, EBUS-TBNA, which facilitates direct diagnosis, is preferred.
PMCID: PMC3045379  PMID: 21364919
12.  CYP1A1 gene polymorphisms as a risk factor for pterygium 
Molecular Vision  2010;16:1054-1058.
Both cytochrome P4501A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) have been demonstrated to be involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs). BaP 7,8-diol 9,10-epoxide (BPDE), an ultimate metabolite of benzo(a)pyrene (BaP), attacks deoxyguanosine to form a BPDE-N2-dG adduct resulting in p53 gene mutations. Our previous report indicated that BPDE-like DNA adduct levels in pterygium were associated with CYP1A1 gene polymorphisms. Therefore, we hypothesize that the genetic polymorphisms of CYP1A1 and GSTM1 increase the risk for pterygium.
Two hundred-five pterygial specimens and 206 normal controls were collected in this study. For the analysis of CYP1A1 and GSTM1 gene polymorphisms, DNA samples were extracted from blood cells and then subjected to restriction fragment length polymorphism and polymerase chain reaction for the determination of mutation and genotype of CYP1A1 and GSTM1.
There was a significant difference between the case and control groups in the CYP1A1 genotype (p=0.0161) but not in GSTM1 (p=1.000). The odds ratio of the CYP1A1 m1/m2 polymorphism was 1.327 (95% CI=0.906–2.079, p=0.135) and the m2/m2 polymorphism was 1.647 (95% CI=1.154–2.350, p=0.006), compared to the m1/m1 wild-type genotype. The GSTM1 polymorphisms did not have an increased odds ratio compared with the wild type.
In conclusion, a CYP1A1 polymorphism is correlated with pterygium and might become a marker for the prediction of pterygium susceptibility.
PMCID: PMC2893055  PMID: 20596254
13.  The Influence of Aging on Pharyngeal Collapsibility During Sleep 
Chest  2007;131(6):1702-1709.
Aging increases vulnerability to obstructive sleep apnea (OSA), but the underlying mechanisms remain unclear. Recent data in awake healthy volunteers show a decrease in the genioglossus negative pressure reflex and anatomic compromise with increasing age, suggesting an age-related predisposition to pharyngeal collapse. However, aging effects on pharyngeal collapsibility have not been studied extensively during sleep. We tested the hypotheses that upper airway closing pressure (PCLOSE) and the increase in pharyngeal resistance during sleep (primary outcomes) as well as measures of arousal threshold (secondary outcomes) increase with age.
We studied 21 healthy individuals (8 women [mean (± SD) age, 36 ± 18 years] and 13 men [mean age, 41 ±23 years]) who were between 18 and 75 years of age. During overnight polysomnography, we measured nasal pressure (Pmask) and epiglottic pressure (Pepi) during stage 2 sleep before and after airway occlusion (external valve) until arousal. Pclose was defined as the pressure at which Pmask plateaued despite further decreases in Pepi.
Increasing age was correlated with both pharyngeal collapsibility ([Pclose] r = 0.69; p < 0.01) and an increase in pharyngeal resistance during sleep (r = 0.56; p < 0.01) independent of body mass index (BMI) and gender. There was no evidence for an effect of age on arousal threshold after airway occlusion during stage 2 sleep.
Older age is associated with increased pharyngeal airway collapsibility during sleep independent of gender and BMI. These data may at least partially explain the mechanisms underlying the predisposition for pharyngeal collapse in the elderly.
PMCID: PMC2278166  PMID: 17413053
aging; collapsibility; dilator muscles; integrity; sleep-disordered breathing; upper airway

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