Shifting and reducing breathing disturbance in patients with very severe obstructive sleep apnea by modified Z-palatoplasty with one-layer closure in one-stage multilevel surgery

Very severe obstructive sleep apnea (OSA) with apnea–hypopnea index (AHI) ≥ 60 events/h differs in several areas from OSA with other severities, including having a low-level daytime partial pressure of oxygen and residual on-CPAP (continuous positive airway pressure) AHIs greater than 20/h. Patients with very severe OSA show narrow retroglossal space and confined framework, which is difficult to be enlarged via conventional Uvulopalatopharyngoplasty (UPPP) surgery, resulting in poor response to non-framework surgeries. Our latest report showed efficacy and efficiency for subjects undergoing modified Z-palatoplasty (ZPP) with one-layer closure in a one-stage multilevel surgery. It is unclear whether and how this procedure could help patients with very severe OSA characterized with confined framework. From Mar. 2015 to May 2018, we enrolled 12 patients with very severe OSA receiving one-stage multi-level surgery with modified ZPP with one-layer closure, CO2 laser partial tongue-base glossectomy, and bilateral septomeatoplasty. Our results show that the surgery reduced AHI from 73.8 ± 10.7 to 30.8 ± 23.2 events/h and achieved a mean AHI reduction of 58.3% (p < 0.001 against 0 reduction or no surgery). The surgery shifted components of the breathing disturbances. It reduced more apnea than hypopnea and might convert some apnea to hypopnea.

www.nature.com/scientificreports/ However, the similar confined framework is commonly seen in some patients with only mild OSA. It hints an opportunity for a non-framework surgery. As a non-framework surgery, modified ZPP with one-layer closure in a one-stage multilevel surgery 26 has revealed efficacy and efficiency as that proposed by Friedman and colleague since 2004 [27][28][29] . It is unclear whether and how this technique could help patients with very severe OSA. Reducing OSA severity may help in its consequences, e.g., hypertension 30 , cognitive deficits 31,32 , and cardiovascular disorders [33][34][35] . Reducing desaturation might improve coexisting medical conditions. It is unknown how this surgery may improve the severity and desaturation. Smaller body mass index (BMI) and preoperative AHI were reported good predictors for the surgical outcome 36 . Better surgical response has been described in patients with smaller BMI (< 30) or smaller AHI (< 60) 36 . It is unclear whether they stay good predictors in the category of very severe OSA. Here in this study, we analyzed the component shifts and tested the statistical significance of pre-and post-operative sleep parameters for very severe OSA patients whose AHIs are higher or equal to 60 events/h. We also tested the effectiveness of these two predictors.

Materials and methods
From Mar. 2015 to May 2018, we enrolled subjects with very severe OSA who met these criteria to the study: • Age ≥ 20 years • Unsuccessful or refusal of CPAP • AHI ≥ 60 events/h • Received a one-stage multi-level sleep surgery with the modified ZPP performed with one-layer closure, CO2 laser partial tongue-base glossectomy, and bilateral septomeatoplasty • Available preoperative and postoperative polysomnography (PSG) for AHI measurement We performed preoperative endoscopic evaluation to figure the anatomical stage 37 . Patients were not selected for surgery by any other criteria unlisted above. Epworth Sleepiness Scale (ESS) that comprises 8 4-point scale (0-3) inquiries was used to measure daytime sleepiness, with the total score ranging from 0 to 24. The higher the ESS score, the more that individual's daytime sleepiness in everyday life. Modified ZPP with one-layer closure was carried out as illustrated in our earlier report 26 . Open tongue-base resection was completed with transoral (CO2) laser microsurgery for hypopharyngeal obstruction according to the preoperative endoscopic assessment. After the surgery, we cared all patients for in general ward areas with an oximeter monitor. Intravenous Dynastat twice daily was prescribed for 1-3 days. No intravenous or oral narcotics were given to prevent respiratory depression.
We used the percentage of reduction in mean AHI as the primary measure of surgical efficacy 38 to compare with the results across most studies in the literature. It measures the mean change in AHI compared to the mean AHI before surgery. Mean and standard deviation summarized the pre-and post-operative AHI. We performed a paired t-test to examine the change in AHI against no change after the surgery. We examined other associated sleep parameters, including obstructive apnea index (OAI), minimum oxyhemoglobin saturation of pulse oximetry (SpO2), mean SpO2, desaturation index, and mean desaturation with a paired t-test. Postoperative care and complications were also reported, including suture dehiscence and bleeding. A p-value smaller than 0.05 was deemed significant.
We calculated the correlation coefficient between each of preoperative BMI and AHI vs. AHI reduction to test these two predictors. To clarify the effect of BMI change on AHI reduction, we computed individual BMI change (postoperative BMI-preoperative BMI in PSG records) then calculated the correlation coefficient between individual BMI change and AHI reduction. The statistical significance was tested as α = 0.05.
Ethical approval. The Institutional Review Board (IRB) of Chang Gung Medical Foundation, Taiwan approved the study methods and protocols (IRB number: 201800948B0). We performed the study in accordance with Good Clinical Practice and the applicable laws and regulations. As a retrospective cohort study, the IRB approved the waiver of the participants' consent.

Results
Ten male and 2 female patients with very severe OSA aged between 25 and 59 years were enrolled to this work. The mean BMI was 28.1 with a standard deviation of 3.3 kg/m 2 . All patients received the 3 procedures in the multilevel sleep surgery listed above. Two and 1 patients underwent routine endoscopic sinosurgery and adenoidectomy, respectively. A PSG followed about 5 months (159 ± 59 days, mean with one standard deviation) after the surgery. Table 1 detailed the individual pre-and post-operative AHI, Friedman anatomic stage, and the surgeries performed.
There was an event of left inferior tonsil wound hemorrhage in case 5 that resulted in an unplanned return to the operating room. No other major dehiscence or airway complication arose. The mean ESS score declined from 9.67 ± 5.23 to 7.83 ± 5.11. However, the difference did not reach statistical significance (p = 0.39 from a paired t-test). Scatter plots in Fig. 6 summarize the correlation tests of the two preoperative predictors. There was no statistical correlation between either of these two predictors and AHI reduction (r = − 0.12, p = 0.71 and r = 0.118, p = 0.714, respectively). Individual changes of BMI and AHI before and after the surgery were illustrated in Fig. 7. Although more patients (9 out of 12) lost weight after the surgery, BMI change was not statistically correlated with AHI reduction (r = 0.54, p = 0.07).

Discussion
The results show that the multilevel surgery reduced AHI from 73.8 to 30.8 events/h, resulting in an AHI reduction of 58.3% (p < 0.001). It cut desaturation index from 65.1 to 24.1events/h (p < 0.001) and mean desaturation from 10.8 to 5.8% (p = 0.007). The surgery improved mean SpO2 from 92.1 to 95.0% (p = 0.0427) and minimum SpO2 from 70.3 to 80.4% (p = 0.0088). These results would help us on decision making with patients with very www.nature.com/scientificreports/ severe OSA with residual on-CPAP AHIs, or have a low level of daytime PaO2 but refuse the proposed direct skeletal surgery 13 , bariatric surgery 23 , or tracheostomy 24 , or refuse use of CPAP device. A majority (83%) of the patients improved from the very severe category to milder ones and might reduce its comorbidity (e.g., [30][31][32][33][34][35] ). The rest (17% or 2 out of 12 patients) remained in the very severe group. The AHI made worse from 62.6 to 77.6 events/h after the surgery in case 7 and a little lessened from 85.4 to 68.6 events/h in case 6 ( Table 1). To further understand the change made by the surgery in these 2 patients, we looked into matters of the PSGs before and after the surgery. In case 7 (the subject with worsened AHI after the surgery), the apnea part (i.e., OAI), improved from 38.6 to 31.9 events/h, and his minimum SpO2 improved from 50 to 84%. In case 6, the OAI reduced from 73 to 1.3 events/h, and his minimum SpO2 increased from 56 to 71%.
Minimum oxygen (O2) saturation has been listed as one of the main sleep-disordered breathing parameters besides AHI (e.g., see 17,29,37,39 ) or used as one criterion to classify the severity of OSA (e.g., see [40][41][42] ). So, we analyzed individual changes of minimum SpO2 in addition to OAI (Fig. 4). The mean OAI reduced from 44.03 to 5.79 events/h with a reduction rate of 86.8%, which showed that the OAI reduction (86.8%) was better than AHI reduction (58.3%). These results showed that the surgery reduced more portion of obstructive apnea than hypopnea. The sum of apneas and hypopneas per hour did not cut as many as the sum of apneas per hour-some  To relate the surgical outcome with non-framework sleep surgeries in the literature, we reviewed 253 OSA related articles. Among them, 32 enrolled subjects with very severe OSA. Four provided detailed subject information and allowed us to calculate the mean AHI reduction. In Jacobowitz's report 43 , mean AHI reduction was 77.1/h after UPPP with or without genioglossus advancement, hyoid suspension, or tongue-base radiofrequency treatment (n = 9), calculated from their Table 4. The mean AHI reduction was 38.2/h after UPPP (n = 6), computed from Table 1 in Walker's study 40 ; 14.4/h after UPPP and hyoid advancement with or without mandibular osteotomy with genioglossus advancement (n = 11), reckoned from Table 2 in Vilaseca report 9 . The mean RDI reduction was 42.2/h after UPPP and midline glossectomy with or without septomeatoplasty (n = 10), calculated from Table 1 in Mickelson's study 44 . Figure 8 presents the comparison of the present study with these reports.
Some studies recommend postoperative prudence treatment for patients with very severe OSA due to a higher risk of postoperative oxygen desaturation (e.g., Pang, K. P., Siow, J. & Tseng, P. 42 ). They usually allocated these patients to the surgical intensive care unit (SICU) after the surgery (e.g., Rotenberg,B. 46 ). In the present study, we cared for all patients in general ward areas with an oximeter monitor for 1 to 3 days while they breathe via the mouth because of nasal packing. No immediate or airway complication arose.
Some studies (e.g., Lin, H. S. et al. 36 ) disclosed that BMI or preoperative AHI predicts surgical outcome. There was no correlation either between BMI and AHI reduction or between preoperative AHI and AHI reduction in this study. It needs future studies to find a good predictor for patients with very severe OSA.

Conclusions
Our results show that modified Z-palatoplasty with one-layer closure in the one-stage multilevel surgery achieved a mean AHI and OAI reduction of 58.3% and 86.8% (p < 0.001), respectively. It reduced the frequency (desaturation index) and level (mean desaturation) of desaturation and improved mean and minimum oxygen saturation. Analyses show a shift in the components of breathing disturbances. This non-framework surgery reduced more apnea than hypopnea and might convert some apnea to hypopnea.  www.nature.com/scientificreports/

Data availability
The raw data in the current study are available from the supplementary information. www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.