Clinical Neurophysiology 127 (2016) 544–550

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Improvement of baroreflex sensitivity in patients with obstructive sleep apnea following surgical treatment Chih-Cheng Huang a, Wei-Che Lin b, Hsiu-Ling Chen b, Michael Friedman c,d, Meng-Chih Lin e,g, Hsin-Ching Lin f,g,⇑,1, Cheng-Hsien Lu a,h,i,⇑,1 a

Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan Department of Otolaryngology and Bronchoesophagology, Rush University Medical Center, Chicago, IL, USA d Department of Otolaryngology, Advocate Illinois Masonic Medical Center, Chicago, IL, USA e Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan f Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan g Sleep Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan h Department of Biological Science, National Sun Yat-Sen University, Kaohsiung, Taiwan i Department of Neurology, Xiamen Chang Gung Memorial Hospital, Xiamen, Fujian, China b c

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Article history: Accepted 16 May 2015 Available online 3 June 2015 Keywords: Obstructive sleep apnea Baroreflex sensitivity OSA surgery Palato-pharyngoplasty Autonomic function

h i g h l i g h t s  Patients with obstructive sleep apnea have depressed baroreflex sensitivity that may contribute to the

higher rate of cardiovascular morbidity and mortality of these patients.  This study demonstrates a significant correlation between baroreflex sensitivity and apnea–hypopnea

index in patients with obstructive sleep apnea.  This study shows that surgical treatment improves both the major parameters of polysomnography

and the depressed baroreflex sensitivity.

a b s t r a c t Objective: Depressed baroreflex sensitivity (BRS) have been reported in patients with obstructive sleep apnea (OSA). This study aimed to determine if surgery can improve the clinical outcomes by investigating changes in BRS and in other cardiovascular autonomic parameters. Methods: Eighty-one OSA patients were enrolled. They were classified as mild OSA if their apnea– hypopnea index (AHI) was 5–15, moderate OSA if their AHI was 15–30, and sever OSA if their AHI was >30. Twenty-three subjects with AHI < 5 were recruited as controls. For patients who received surgery, polysomnography (PSG) and autonomic tests were evaluated upon enrollment and six-months after surgery. Results: The patient number for mild, moderate, and severe OSA was 22, 22, and 37, respectively. BRS on enrollment showed significant difference among the four groups, with the highest BRS in the control group, follow by the mild, moderate, and severe OSA groups. There were significant correlations between BRS and all PSG parameters. The depressed BRS significantly improved after surgery. Conclusions: Surgical modifications of the upper airways can improve the depressed BRS in OSA patients. Significance: The study offers the promise that surgical treatment for OSA not only improves the index of PSG, but also reduces the possibility of cardiovascular risk. Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

⇑ Corresponding authors at: Department of Otolaryngology, Chang Gung Memorial Hospital, 123, Ta Pei Road, Niao Sung District, Kaohsiung, Taiwan. Tel.: +886 7 7317123x2283 (H.-C. Lin). Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan (C.-H. Lu). E-mail addresses: [email protected] (H.-C. Lin), [email protected], [email protected] (C.-H. Lu). 1 Drs. Cheng-Hsien Lu and Hsin-Ching Lin contributed equally to this work. http://dx.doi.org/10.1016/j.clinph.2015.05.022 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

C.-C. Huang et al. / Clinical Neurophysiology 127 (2016) 544–550

1. Introduction Obstructive sleep apnea (OSA) is the periodic reduction or cessation of airflow during sleep. The syndrome is associated with loud snoring, recurrent upper airway obstruction, recurrent apneas/hypopnea, oxygen desaturation, and arousals during sleep. Baroreflex is a key mechanism involved in blood pressure (BP) homeostasis. It maintains a stable BP by adjusting heart rate (HR) (cardiovagal component) and total peripheral resistance (adrenergic component). Several studies demonstrate that OSA patients have depressed baroreflex sensitivity (BRS) (Carlson et al., 1996; Narkiewicz et al., 1998; Parati et al., 1997; Ryan et al., 2007) and such dysfunction may contribute to the higher rate of cardiovascular morbidity and mortality reported in these patients (Marin et al., 2005; Partinen et al., 1988). Continuous positive airway pressure (CPAP) is the primary treatment of OSA. Although studies on CPAP compliance vary from 28% to 80% (Haniffa et al., 2004; Lin et al., 2007), there is a consensus that a certain numbers of OSA patients cannot or will not use CPAP. Surgery for OSA is not a substitute for CPAP but is a salvage procedure for those who failed CPAP and other conservative therapies and have no other options. Concepts of surgical treatment for OSA are based on reducing the volume of redundant tissues, stiffening the flaccid soft palate, and suspending the collapsed tongue base to maintain airway patency for improving symptoms and reducing the sequelae of OSA. The efficacy and safety of multi-level surgery has been demonstrated in literature (Lin et al., 2008, 2010, 2011, 2014). Some studies show improved BRS after CPAP treatment (Bonsignore et al., 2002, 2006; Noda et al., 2007; Ryan et al., 2007; Tkacova et al., 2000) although most of these reports have limited case numbers. However, except for a study enrolling children as study subjects (Crisalli et al., 2012), little information is available on the effects of surgical modification for adult patients with OSA in terms of BRS. This study tested the hypothesis that the OSA surgery can not only reduce the index of apneas/hypopnea but also improve BRS. The successful clinical translation of these approaches offers the promise that the surgical treatment for OSA not only improves the index of PSG, but also reduces the possibility of cardio- and/or cerebro-vascular risk. 2. Patients and methods 2.1. Study design This is a single-center, prospective case-control study conducted at Kaohsiung Chang Gung Memorial Hospital, a medical center and main referral hospital serving an area with the population of 3 million in southern Taiwan.

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circadian variations. Blood samples were obtained for biochemical analyses. All of these studies were repeated 6 months after surgery for patients with OSA. 2.3. Polysomnography study All-night attended comprehensive diagnostic sleep studies were performed at the hospital’s Sleep Center, in a temperaturecontrolled and sound-attenuated room. Electroencephalography, submental electromyography, and electro-oculography were recorded by surface electrodes using standard techniques. Nasal and oral airflow were recorded by thermistors. Oxygen saturation was measured by pulse oximetry. Sleep stage scoring was done in 30-s intervals by experienced technicians according to the standard criteria (Rechtschaffen and Kales, 1968). By definition, obstructive apnea was a cessation of airflow for at least 10 s with effort to breathe during apnea. Obstructive hypopnea was defined as an abnormal respiratory event with at least a 30% reduction in thoraco-abdominal movement or airflow when compared to the baseline, lasting at least 10 s, and with P4% oxygen desaturation (Kushida et al., 2005). The apnea–hypopnea index (AHI) was defined as the total number of apneas and hypopneas per hour of electroencephalographic sleep, while OSA was defined as AHI > 5 per hour. The severity of sleep-disordered breathing was classified according to the number of apneas and hypopneas during sleep. Subjects with AHI 5–15 were classified as mild OSA, AHI 15–30 as moderate OSA, and AHI > 30 as severe OSA (Sleep, 1999). The controls had AHI < 5. All PSGs were scored and read by an experienced physician who was blinded to the patients’ participation in the study. 2.4. Inclusion and exclusion criteria Eighty-one patients with OSA and 23 control subjects were recruited. Patients were excluded if they suffered from moderate-to-severe heart failure (New York Heart Association (NYHA) class III and IV); had any type of arrhythmia that prevented measurement of autonomic indices, or pacemaker implantation due to any cause; had underlying medical diseases known to affect autonomic system, such as diabetes mellitus and chronic renal failure; had neoplastic disorders; had stroke history, critical carotid stenosis requiring carotid end-arterectomy or stenting, myocardial infarction, or coronary artery diseases status post-percutaneous trans-luminal coronary angioplasty or bypass surgery; and had central or peripheral disorders known to affect autonomic system, such as Parkinson’s disease, diffuse Lewy-body disease, multiple system atrophy, and pure autonomic failure. 2.5. Surgical procedures

2.2. Study protocol The hospital’s Institutional Review Committee on Human Research approved the study protocol (CGMH IRB #100-4351B) and all of the study subjects provided informed consent. Each patient participated in a detailed interview regarding his/her personal disease and physical examination that included measurements of body height and weight. All of the subjects then underwent a comprehensive sleep study, polysomnography (PSG), for the diagnosis of OSA and cardiovascular autonomic survey, including deep breathing and Valsalva maneuver (VM) tests as described by Low (Low, 2003). A 5-min resting recording of ECG was also done for spectral analysis of HR variability. These autonomic tests were done in the morning before noon to exclude the possible influence of

All of the procedures were performed by the co-corresponding author (H-C Lin) under general anesthesia and with oro-tracheal intubation. The techniques used were determined upon the discretion of the treating sleep surgeon based on the severity of OSA with PSG and conditions of upper airway abnormality as examined by flexible fibroscopy. The modified uvulo-palato-pharyngoplasty (UPPP), or Z-palatopharyngoplasty (ZPPP), was used for the retro-palatal obstruction. ZPPP was designed to create the necessary supero-anterolateral tension and further widen the pharynx. It has been demonstrated to increase the surgical success rate and ameliorate some possible complications of traditional UPPP. Trans-oral endoscopic tongue base tissue volume reduction with radiofrequency/coblator was performed for the retro-lingual obstruction. (Lin et al., 2008, 2010, 2014).

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2.6. Cardiovascular autonomic assessment HR was derived from continuously recorded standard three-lead ECG (Ivy Biomedical, model 3000; Branford, CT) while arterial BP was continuously measured using beat-to-beat photoplethysmographic recordings (Finameter Pro, Ohmeda; Englewood, OH). The following parameters were obtained through tests computed by Testworks (WR Medical Electronics Company, Stillwater, MN): HR response to deep breathing (HR_DB), valsalva ratio (VR), and BRS. The detailed computing of HR_DB and VR were as described by Low (2003). To quantify BRS, a linear regression analysis was performed between systolic BP and RR interval (RRI) changes during the early phase II of VM. In this phase, there was a progressive decrease in systolic BP due to reduced preload (venous return) and stroke volume, with associated tachycardia (gradual shortening of RRI) (Imholz et al., 1988). Beat-to-beat RRI changes were interpolated using a third-order polynomial and were re-sampled with 0.5-s intervals. The signals were then transformed to the frequency domain with fast Fourier transform by using 512 samples. Spectral powers were divided into three frequency domains, high frequency (HF, 0.15–0.4 Hz), low frequency (LF, 0.04–0.15 Hz), and very low frequency (VLF, 0–0.04 Hz). The ratio between powers of LF and HF (LF/HF ratio) was taken as an index of sympatho-vagal balance. 2.7. Biochemical analysis Blood samples were obtained by ante-cubital vein puncture in a fasting, non-sedative state, and were analyzed by the hospital’s central laboratory for complete blood count analysis, glycohemoglobin (HbA1c), high sensitive C-reactive protein (hs-CRP), and lipid profiles, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride.

The associations between measurements were evaluated by Pearson correlation tests for normally distributed data or by Spearman non-parametric test for data with skewed deviation. Third, continuous variables at two time periods (upon enrollment and six months after surgery) were compared by paired t-test for normally distributed data or by non-parametric Wilcoxon signed rank test for data with skewed deviation. Statistical significance was set at p < 0.05. All statistical analyses were conducted using the IBM SPSS software package, version 17 (IBM, Inc., Armonk, NY).

3. Results 3.1. Baseline characteristics of the study patients The 104 study subjects were divided into four groups, including the control group and the groups of patients with mild, moderate, and severe OSA, respectively. There were 23, 22, 22, and 37 patients in each group, respectively. Based on the baseline characteristics and results of PSG (Table 1), the characteristics of the four groups were similar as regards age (p = 0.449), gender (p = 0.201), and body mass index (p = 0.644). Since these subjects were grouped according to AHI, data on AHI and other PSG parameters progressively worsened from the groups of normal controls to those with mild, moderate, and severe OSA. 3.2. Comparison of baseline characteristics of biochemical laboratory data The baseline biochemical laboratory data (Table 2) revealed that except for hs-CRP, which showed borderline significant difference among the four groups, all of the other biochemical data were similar among the four groups.

2.8. Statistical analysis 3.3. Comparison of the cardiovascular autonomic parameters Continuous variables were expressed as mean ± SD or median (inter-quartile range). Three separate statistical analyses were performed. First, continuous variables among the four groups (the control, and mild, moderate, and severe OSA groups) were compared using one-way ANOVA, followed by post hoc multiple comparison procedure. Non-normal-distributed variables were compared by Kruskal–Wallis test. Second, correlation analysis was used to explore the relationship between autonomic parameters and laboratory apnea/hypopnea parameters and variables like age and body mass index (BMI).

There were significant differences in BRS among the four groups (Table 3). The control group had largest BRS while the group with severe OSA had the smallest. For the other cardiovascular autonomic parameters like HR_DB, VR, and LF/HF ratio, there were no significant differences among the four groups. There were significant differences in diastolic BP among the four groups. By Tukey post hoc multiple comparisons, the control group had significantly lower diastolic BP than the severe OSA group. In terms of systolic BP, although the control group had the lowest systolic BP and the

Table 1 Demographic data and polysomnography results for groups of control subjects and OSA of different severity.

Age Gender (F/M) BMI, kg/m2 AHI-TST AHI-REM AHI-NREM mO2 < 90% Average O2 Lowest O2 De-saturation index Arousal index Snoring index ESS

Controls (n = 23)

Mild OSA (n = 22)

Moderate OSA (n = 22)

Severe OSA (n = 37)

p value

38.3 ± 9.4 5/18 24.4 ± 2.5 2.3 [1.1, 3.5] 4.5 [1.6, 8.4] 1.7 [0.5, 2.5] 0.0 [0.0, 0.4] 96.7 ± 1.1 89.9 ± 4.8 0.0 [0.6, 1.3] 11.3 [5.7, 16.5] 87 [13, 245] 9.0 [5.0, 13.0]

42.9 ± 9.4 3/19 25.3 ± 2.8 10.3 [9.2, 11.7] 19.0 [7.6, 33.3] 6.3 [4.4, 8.7] 0.8 [0.1, 1.7] 96.6 ± 1.1 88.1 ± 2.6 4.8 [2.8, 5.6] 15.4 [8.4, 27.1] 331 [181, 520] 7.5 [3.8, 11.3]

39.5 ± 11.2 5/17 25.0 ± 3.2 20.8 [17.5, 26.3] 35.5 [23.2, 4.7] 21.2 [13.2, 23.9] 1.4 [0.6, 2.4] 96.2 ± 0.9 81.88.4 12.3 [6.1, 14.8] 19.7 [14.1, 39.5] 325 [164, 622] 9.5 [7.8, 12.3]

40.4 ± 9.4 2/35 25.0 ± 1.6 56.3 [45.5, 63.6] 54.9 [41.9, 63.9] 56.8 [46.3, 64.9] 11.1 [4.3, 24.2] 94.5 ± 1.6 73.0 ± 9.9 49.2 [32.4, 57.7] 51.2 [24.0, 73.4] 389 [251, 491] 8.0 [5.5, 13.0]

0.449 0.201 0.644

Improvement of baroreflex sensitivity in patients with obstructive sleep apnea following surgical treatment.

Depressed baroreflex sensitivity (BRS) have been reported in patients with obstructive sleep apnea (OSA). This study aimed to determine if surgery can...
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