Obstructive sleep apnea syndrome (OSAS) affects

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1 A comparison of radiofrequency treatment schemes for obstructive sleep apnea syndrome DAVID L. STEWARD, MD, EDWARD M. WEAVER, MD, MPH, and B. TUCKER WOODSON, MD, Cincinnati, Ohio, Seattle, Washington, and Milwaukee, Wisconsin OBJECTIVES: We sought to determine whether increasing temperature-controlled radiofrequency tissue ablation (TCRFTA) treatments provide incremental improvement in outcomes of obstructive sleep apnea syndrome (OSAS). METHODS: Twenty-six subjects randomized to TCRFTA treatment for mild to moderate OSAS were studied at baseline, 1 month after 3 tongue treatments (interim), and then 2 months after 2 additional tongue and palate treatments (final). Outcomes included OSA-specific quality of life (Functional Outcomes of Sleep Questionnaire [FOSQ] and Symptoms of Nocturnal Obstruction and Related Events [SNORE25]), daytime sleepiness, and reaction times (slowest, median, and fastest). RESULTS: Interim outcomes were significantly better than baseline for FOSQ and SNORE25 (P < 0.05), with a trend toward improvement for sleepiness (P 0.06). Final outcomes were significantly better than interim outcomes for FOSQ, sleepiness, slowest From the Department of Otolaryngology Head and Neck Surgery, University of Cincinnati (Dr Steward), Department of Otolaryngology, University of Washington (Dr Weaver), and Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin (Dr Woodson). Presented at the Annual Meeting of the American Academy of Otolaryngology, Orlando, FL, September 21-24, Data collection was supported in part by a research grant from Gyrus-ENT. The authors have no other conflict of interest or other financial relationship with the device manufacturer. Dr Weaver was supported by the Robert Wood Johnson Clinical Scholars Program during project development. Dr Weaver is currently supported by a career development award (HL068849) from the National Heart, Lung, and Blood Institute and by a career development scholars award from the American Geriatrics Society. Reprint requests: David L. Steward, MD, Department of Otolaryngology HNS, ML0528, University of Cincinnati, Cincinnati, OH ; , david.steward@ uc.edu /$30.00 Copyright 2004 by the American Academy of Otolaryngology Head and Neck Surgery Foundation, Inc. doi: /j.otohns and median reaction time (all P < 0.05), and nonsignificantly improved for SNORE25 (P 0.30) and fastest reaction time (P 0.18). All final outcomes were improved from baseline (P < 0.05). CONCLUSIONS: Three TCRFTA tongue treatments significantly improved OSA-specific quality of life. An additional 2 TCRFTA tongue and palate treatment sessions further significantly improved quality of life and reaction times. (Otolaryngol Head Neck Surg 2004;130: ) Obstructive sleep apnea syndrome (OSAS) affects at least 2% to 4% of middle-aged adults 1 and results in significant mortality 2 and morbidity from cardiovascular disease, 3 quality of life deficits, 4 and performance deficits due to loss of alertness. 5 Fortunately, successful treatment can reverse these risks of OSAS. 2,5 Although provision of continuous positive airway pressure (CPAP) remains the gold standard therapy for OSAS, many patients use the device for less than half of recommended sleep time. 6 Surgery has the advantage of not being dependent on nightly device use, but it often produces incomplete physiologic correction. Most operations are associated with significant patient morbidity. Temperature-controlled radiofrequency tissue ablation (TCRFTA) improves quality of life and reaction time with minimal morbidity, as shown in a randomized sham placebo controlled trial of tongue and palate treatment for mild to moderate OSAS. 7 Numerous other studies have demonstrated improvement in OSAS after tongue or palate TCRFTA using various treatment strategies 8-10 and with less morbidity than established palate surgery. 10,11 TCRFTA has the advantage of office-based surgery using only local anesthesia but requires multiple treatment sessions. Studies of different palate TCRFTA techniques suggest that increased energy delivery is significantly correlated with successful snoring treatment, but 579

2 580 STEWARD et al May 2004 the optimal number of treatment sessions for successful treatment of OSAS remains unknown. Our hypothesis is that increasing TCRFTA treatment sessions add incremental benefit for patients with OSAS. To test this hypothesis, we analyzed baseline, interim, and final evaluation data for the TCRFTA treatment group from our previously published randomized controlled trial. 7 METHODS Study Design A subgroup analysis of data from a 2-institution randomized controlled trial 7 was performed to test the hypothesis that an increased number of TCRFTA treatments is increasingly effective for improvement of clinically important outcomes in patients with mild to moderate OSAS. Participants Eligible subjects were adults with excessive daytime sleepiness and untreated mild or moderate OSAS without morbid obesity, who were randomized to the active TCRFTA arm of the original study. Detailed inclusion and exclusion criteria were described previously. 7 One patient included initially was excluded before TCRFTA treatment. Three patients failed to complete all planned TCRFTA treatments (10% dropout rate). Three patients who completed all TCRFTA treatments had incomplete outcomes data; all available data were analyzed for all subjects randomized to active TCRFTA treatment. Subjects randomized to sham placebo or nasal CPAP treatment were not included in this subgroup analysis. Subjects were recruited directly from the academic otolaryngology practices and from poster and newspaper advertisements. This study was designed and performed with approval from local institutional review boards. All patients gave informed consent. Polysomnography/Sleep Studies Screening sleep studies included home Autoset PDS (ResMed Corp, San Diego, CA) or full inlaboratory polysomnography (PSG) (if performed within 1 year of enrollment). All subjects underwent a subsequent baseline full PSG (unless full in-laboratory PSG was performed within 6 months of enrollment). Apnea was defined as cessation of inspiratory airflow of 10 seconds or greater. Hypopnea was defined as a reduction of inspiratory airflow of 10 seconds or greater, with an associated 4% decrease in oxyhemoglobin saturation or an electroencephalographic arousal. Intervention TCRFTA was performed with the Somnoplasty radiofrequency generator (Gyrus-ENT, Memphis, TN). Five tongue and 2 palate sessions were planned for each active subject. Subjects were treated perioperatively with oral antibiotics, prednisone, antiseptic oral rinse, analgesic (as needed), and nonsteroidal antiinflammatory drugs (as needed). A local anesthetic mixture (2.5 ml of 2% lidocaine with 1:100,000 epinephrine, 2.0 ml of normal saline, and 0.5 ml of 8.4% sodium bicarbonate) was injected into each tongue treatment site, and 1% lidocaine with 1:100,000 epinephrine (1 to 2 ml) was injected into each palate site. Radiofrequency energy was delivered to create nonoverlapping lesions in 2 or 3 tongue sites (1000 J or 750 J, respectively, per site; target temperature 85 C; maximum power 10 W) per tongue treatment session, which occurred at 4-week intervals. Radiofrequency energy was delivered to create 1 midline and 2 lateral lesions (nonoverlapping) to the soft palate (650 J and 325 J, respectively) in each palate treatment session. When tongue and palate sessions were combined, the subject was offered overnight hospital admission. One month after completion of 3 tongue treatment sessions, baseline measures (except PSG) were repeated (interim evaluation). Two additional tongue and palate treatment sessions were performed, and baseline measures were repeated 2 months after the last treatment session (final evaluation). Outcomes The outcome measures were chosen to represent meaningful measurements of quality of life, sleepiness, and reaction times, measured 1 month following interim treatment and 2 months following final treatment. Surrogate outcome measures (eg, PSG parameters) were included in the parent study. 7 OSAS-specific quality of life was measured with 2 validated questionnaires: 1) Functional Outcomes of Sleep Questionnaire (FOSQ) 15 and 2) Symptoms of Nocturnal Obstruction and Related Events (SNORE25), formerly the OSA

3 Volume 130 Number 5 STEWARD et al 581 Table 1. Baseline characteristics Variable Norm Mean SD Range Age (y) to 63 Gender (% male) 89.7 Body mass index (kg/m 2 ) to 34.2 Neck circumference (cm) to 45.7 Apnea-Hypopnea Index (events/hr) to 43.8* Apnea Index (events/hr) to 37.0 Lowest saturation (%) to 97.0 *Apnea-Hypopnea Index inclusion criteria were based on screening sleep study. Baseline Apnea-Hypopnea Index was provided with a subsequent polysomnography, which sometimes yielded a different Apnea-Hypopnea Index value. Patient Oriented Severity Index. 16 Daytime sleepiness was measured using the Epworth Sleepiness Scale. 17 Reaction times were measured using the Psychomotor Vigilance Task (PVT-192; Ambulatory Monitoring Inc, Ardsley, NY) with a total test time of 10 minutes and stimulus interval 2 to 10 seconds. 18 Slowest reaction time (SRT) was measured as the mean of the slowest 10% of reaction times. SRT was analyzed as the reciprocal (1/ SRT) to minimize the contribution of very long lapses. 18 Median reaction time and fastest reaction time (mean of fastest 10% reaction times) were also analyzed. Data Management and Statistical Methods Data were collected on case report forms at each site. Copies were mailed to the sponsor s data coordinators, who entered the data and visually checked for accuracy. The principal investigator at each treatment site verified data accuracy. Data were also checked statistically and inconsistencies were resolved with the raw data at each site. Data are presented as the mean SD. Effect sizes were calculated as (posttreatment mean pretreatment mean)/(pretreatment standard deviation) according to Kazis et al. 19 Positive sign denotes improvement with treatment; negative sign denotes worsening. Changes in outcome measures were analyzed using the 1-sided paired t test for normally distributed variables and 1-sided sign test for non-normally distributed variables. Onesided tests were used because improvement with treatment was expected. 7 Normality was tested with the Shapiro-Wilk W test, Shapiro-Francia W test, and combined skewness and kurtosis tests. A variable was considered non-normal if it failed any 1 of these tests. The data were analyzed with Intercooled Stata 7.0 software (Stata Corp, College Station, TX). A value of P 0.05 was considered statistically significant. RESULTS Baseline characteristics are summarized in Tables 1 and 2. In general, the subjects were middleaged overweight men with moderate OSAS. They demonstrated OSAS-related quality of life deficits, excessive daytime somnolence, and impaired reaction time testing. Treatment data are summarized in Table 2. The results for each outcome measure are summarized in Table 3. When compared with pretreatment baseline, 3 tongue base TCRFTA treatment sessions (interim) resulted in significant improvement in FOSQ and SNORE25 (Table 4). A trend toward significant improvement was noted for the Epworth Sleepiness Scale. A small to moderate effect size is seen for 4 of 6 outcomes (Table 4, Fig 1). No significant improvement was noted for the reaction time variables (Table 4). Compared with interim evaluation (after 3 tongue TCRFTA treatments), the final evaluation after 2 additional tongue and palate treatments resulted in significant improvement in FOSQ, Epworth Sleepiness Scale, slowest reaction time, and median reaction time (Table 5). Nonsignificant improvement was noted for SNORE25 and fastest reaction time (Table 5). A small to moderate effect size is seen for most outcomes (Fig 2). The results of comparison of final to baseline data were previously reported in the parent study. 7

4 582 STEWARD et al May 2004 Table 2. Radiofrequency treatment summary Variable Interim: tongue Final: tongue Final: palate No. of sessions No. of lesions/session Time/lesion (sec) (midline) (lateral) Energy/lesion (J) (midline) (lateral) Energy/session (J) Total energy (J) Data are presented as mean SD. Table 3. Summary of outcome measures Outcome measure Baseline Interim Final Functional Outcome of Sleep Questionnaire SNORE Epworth Sleepiness Scale /Slowest reaction time (1/msec) Median reaction time (msec) Fastest reaction time (msec) SNORE25, Symptoms of Nocturnal Obstruction and Related Events questionnaire. Data are presented as mean SD. Table 4. Baseline versus interim outcomes Outcome measure Difference* Effect size P Functional Outcome of Sleep Questionnaire SNORE <0.001 Epworth Sleepiness Scale /Slowest reaction time (1/msec) Median reaction time (msec) Fastest reaction time (msec) SNORE25, Symptoms of Nocturnal Obstruction and Related Events questionnaire. Data are presented as mean SD. *Difference is interim outcome baseline outcome. Effect size is (interim outcome baseline outcome)/(baseline standard deviation). Positive indicates improvement; negative indicates worsening. Subjects with baseline or interim data missing were not included in the effect size calculation. P value based on 1-sided paired t test for comparison of means for normally distributed variables or sign test for comparison of medians for nonnormally distributed variables. P 0.05 is significant (indicated in bold). Statistically significant improvement was noted for all 6 of these outcomes. There were 4 adverse events (3 hematomas, 1 mucosal ulceration), which occurred in 3.1% of all treatment sessions. All 4 events were mild and temporary, and they all occurred during the first treatment session. DISCUSSION The results of this study indicate that 3 tongue base TCRFTA treatment sessions significantly improved OSAS-related quality of life for patients with mild to moderate OSAS. The addition of 2 more tongue and palate TCRFTA treatments further significantly improved OSASrelated quality of life, daytime sleepiness, and reaction times. Although additional TCRFTA treatments add cost and potential patient morbidity beyond the initial 3 tongue treatments, they appear to result in significant improvement in patient-relevant outcomes of OSAS. The risk of adverse events did

5 Volume 130 Number 5 STEWARD et al 583 Fig 1. Effect sizes (baseline interim). Interim effect sizes after 3 tongue treatments over baseline measures. FOSQ, Functional Outcomes of Sleep Questionnaire; SNORE25, Symptoms of Nocturnal Obstruction and Related Events questionnaire; ESS, Epworth Sleepiness Scale; 1/SRT, slowest reaction time (reciprocal); RT, median reaction time; FRT, fastest reaction time. *Statistically significant (P 0.05) effects. Table 5. Interim versus Final Outcomes Outcome Measure Difference* Effect Size P-value Functional Outcome of Sleep Questionnaire SNORE Epworth Sleepiness Scale /Slowest reaction time (1/msec) Median Reaction time (msec) <0.001 Fastest Reaction time (msec) SNORE25 Symptoms of Nocturnal Obstruction and Related Events questionnaire. Data presented as mean standard deviation. *Difference is final outcome interim outcome. Effect size (final outcome interim outcome)/(interim standard deviation). Positive indicates improvement; negative indicates worsening. Subjects with interim or final data missing were not included in the effect size calculation. P value based on one-sided paired t-test for comparison of means for normally distributed variables or sign test for comparison of medians for nonnormally distributed variables. P 0.05 is significant (bold). not increase with the additional 2 tongue and 2 palate treatments, as these additional treatments resulted in no additional adverse events. Of course, individual response to TCRFTA may vary as a result of patient factors and surgical technique. Further study may reveal the maximum number of treatments beyond which the benefits do not outweigh the risks. A significant limitation of this study is that 3 tongue treatments were compared with 2 additional tongue and palate treatments. It is unclear if the subsequent significant improvement was due to the addition of the palate treatments or both tongue and palate. The lack of interim PSG study precluded evaluation of respiratory parameters in this analysis. However, respiratory parameters are surrogate markers of OSAS and may not correlate with improvement in patient-relevant outcomes such as sleepiness, quality of life, and vigilance (reaction time). 20,21

6 584 STEWARD et al May 2004 Fig 2. Effect sizes (interim final). Final effect sizes after 2 additional tongue treatments and 2 palate treatments, over interim measures. FOSQ, Functional Outcomes of Sleep Questionnaire; SNORE25, Symptoms of Nocturnal Obstruction and Related Events questionnaire; ESS, Epworth Sleepiness Scale; 1/SRT, slowest reaction time (reciprocal); RT, median reaction time; FRT, fastest reaction time. *Statistically significant (P 0.05) effects. We hypothesize that partial treatment of tongue obstruction significantly improves quality of life, whereas a certain threshold of treatment is required to achieve significant improvement in sleepiness and reaction time. These hypotheses should be tested in a different sample of patients in a study designed for this purpose. CONCLUSION Three tongue base TCRFTA treatment sessions significantly improve sleep apnea quality of life, a patient-relevant outcome of OSAS. An additional 2 tongue and palate TCRFTA treatment sessions further significantly improve quality of life, sleepiness, and reaction times. Physicians may consider additional TCRFTA treatments for patients who are not cured with 3 tongue treatments alone, especially if there is evidence of improvement. Further study is needed to identify the total number of treatments required to balance maximal benefit with risk of adverse events. The authors would like to thank Colleen Eigel and Laura Brusky for research study coordination and Julie Brown for assistance with manuscript preparation. REFERENCES 1. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328: Marti S, Sampol G, Munoz X, et al. Mortality in severe sleep apnoea/hypopnoea syndrome patients: impact of treatment. Eur Respir J 2002;20: Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342: Flemons WW, Tsai W. Quality of life consequences of sleep-disordered breathing. J Allergy Clin Immunol 1997;99:S Valencia-Flores M, Bliwise DL, Guilleminault C, et al. Cognitive function in patients with sleep apnea after acute nocturnal nasal continuous positive airway pressure (CPAP) treatment: sleepiness and hypoxemia effects. J Clin Exp Neuropsychol 1996;18: Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147: Woodson BT, Steward DL, Weaver EM, et al. A randomized trial of temperature-controlled radiofrequency, continuous positive airway pressure, and placebo for obstructive sleep apnea syndrome. Otolaryngol Head Neck Surg 2003;128: Woodson BT, Nelson L, Mickelson S, et al. A multiinstitutional study of radiofrequency volumetric tissue reduction for osas. Otolaryngol Head Neck Surg 2001; 125:

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