The Laryngoscope C 2014 The American Laryngological, V
Rhinological and Otological Society, Inc.
Impact of Mandibular Advancement Devices on C-reactive Protein Levels in Patients With Obstructive Sleep Apnea Sreeya Yalamanchali, MD; Anna M. Salapatas, BS; Michelle S. Hwang, BS; Thomas R. Pott, MD; Mary E. Lundgren, PhD; Ninos J. Joseph, BS; Michael Friedman, MD Objectives/Hypothesis: To determine the effect of treatment of obstructive sleep apnea (OSA) with custom-made mandibular advancement devices (MADs) on C-reactive protein (CRP) levels in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). Study Design: Case series with chart review. Methods: Charts of consecutive patients fitted with custom-made mandibular advancement devices for treatment of OSAHS between December 2011 and November 2012 were reviewed. Demographics such as age, sex, and body mass index (BMI) were collected. Prefitting and postfitting polysomnograms were reviewed. Pre- and posttreatment apnea–hypopnea index (AHI) and average O2 saturation were compared. Only patients with documented CRP levels determined prior to mandibular advancement device fitting and again after improvement of OSAHS symptoms were included. Results: Forty-nine patients (77.6% male, age 47.4 6 11.7 years, BMI 29.6 6 5.0 kg/m2) were included in this study. Patients initially had elevated CRP levels (2.5 6 1.8 mg/dl), which decreased significantly following use of their custom-made mandibular advancement device (1.9 6 1.3 mg/dl, P 5 0.006) by approximately 24%. AHI decreased significantly from 33.3 6 21.7 pretreatment to 12.1 6 22.3 posttreatment (P < 0.001). Treatment with MADs reduced AHI by approximately 69.3%. Minimum oxygen saturation significantly improved from 85.1% 6 5.9 pretreatment to 90.7% 6 3.6 posttreatment (P < 0.001). Conclusion: Treatment with custom-made mandibular advancement devices significantly reduced elevated CRP levels in patients with mild to severe OSAHS. Therapy achieves reasonable response and cure rates in the observed patients with a significant reduction in AHI. Key Words: Oral appliances, mandibular advancement devices, obstructive sleep apnea, C-reactive protein. Level of Evidence: 4. Laryngoscope, 125:1733–1736, 2015
INTRODUCTION Multiple epidemiological studies have shown a strong link between systemic inflammation and obstructive sleep apnea-hypopnea syndrome (OSAHS).1–4 Repetitive hypoxemic stress from apneic and/or hypopneic episodes results in sympathetic activation, which causes persistent hypertension and increased levels of systemic inflammatory mediators including intercellular adhesion molecules, coagulation factors, and C-reactive protein (CRP).1–6
From the Rush University Medical Center (M.F.); and the Advanced Center for Specialty Care, Advocate Illinois Masonic Medical Center (S.Y., A.M.S., M.S.H., T.R.P., M.E.L., N.J.J., M.F.), Chicago, Illinois, U.S.A. Editor’s Note: This Manuscript was accepted for publication November 6, 2014. Presented as a poster at the 2013 Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Vancouver, British Columbia, Canada, September 29–October 2, 2013. Michael Friedman is the recipient of a research grant from Imthera Medical (San Diego, CA) to conduct a clinical research trial. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Conflict of Interest: None. Send correspondence to Michael Friedman, MD, FACS, Chicago ENT, 30 North Michigan Ave, Suite 1107, Chicago, Illinois 60602. Email: [email protected]
In 2006, the American Academy of Sleep Medicine (AASM) changed their recommendations to include oral appliances (OAs) as first-line therapy for snoring and mild to moderate OSAHS and as salvage therapy for severe OSAHS.7 Oral appliances range from custommade titratable to nontitratable thermoplastic mandibular advancement devices (MADs). Many prior studies have noted a statistically significant decrease in CRP levels after continuous positive airway pressure (CPAP) or surgical treatment of patients with OSAHS,8–14 but thus far no studies have looked at the effect of oral appliances on CRP levels in patients with OSAHS. The objective of this study was to determine the effect of treatment with a custom-made, titratable oral appliance device on serum C-reactive protein levels in patients diagnosed with OSAHS.
MATERIALS AND METHODS Patient Selection
DOI: 10.1002/lary.25061
Approval for this retrospective study was obtained from the Western Institutional Review Board (Puyallup, WA). Charts of 330 consecutive patients diagnosed with OSA and fitted with a custom-made oral appliance device between December 2011 and November 2012 were identified. Patients included in this study either failed CPAP therapy or chose a custom-made MAD
Laryngoscope 125: July 2015
Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
1733
in airflow for 10 seconds relative to basal amplitude. Hypopnea was defined as 50% decrease in the airflow amplitude relative to baseline value, lasting for 10 seconds with the presence of arousal or oxygen desaturation of at least 4%. Patients with AHI 5 to 15 were considered to have mild OSAHS; patients with AHI 15 to 30 were considered to have moderate OSAHS; and patients with AHI 30 were considered to have severe OSAHS (AASM criteria). After treatment, patients were classified using the categories cure, success, or failure. Cure was defined as posttreatment AHI 5. Success was defined as a reduction in AHI of 50% or more and an AHI 20.
Measurement of C-Reactive Protein Fig. 1. TAP 3: Custom-made titratable oral appliance. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] as their primary treatment option. All patients diagnosed with OSAHS, regardless of type of intervention, undergo CRP monitoring at the time of diagnosis. Although CRP testing is recommended in all patients in posttreatment follow-up, there is a high rate of noncompliance for additional CRP testing. Fortynine patients had data available on a baseline polysomnogram (PSG) and a titration PSG with their device, and they completed a blood draw for a CRP level on the day of fitting and after a minimum of 30 days of treatment with their device. Patients with an initial CRP level >10 were excluded. Demographic information including age, sex, and body mass index (BMI) was collected.
Mandibular Advancement Device Fitting All patients were fitted with the Thorton Adjustable Positioner 3 (TAP 3; Airway Management, Inc., Dallas, TX) by a doctor of dental medicine. The TAP 3 is a custom-made, two-piece appliance that fits over the upper and lower teeth (Fig. 1). Alginate impressions of upper and lower dental arches were recorded and poured in dental stone and sent to the dental arts laboratory. Once the custom-made TAP 3 was ready, patients were refitted with the oral appliance to ensure a comfortable fit. The TAP 3 has an anterior dial that allows for adjustment of the device to achieve maximum comfort and efficacy. Each turn is equal to 0.25 mm of additional jaw protrusion.
Polysomnography All patients had a reported 1-night, baseline formal laboratory polysomnographic evaluation and a follow-up titration study with their custom-made device in the same sleep lab. Apnea–hypopnea index (AHI) and minimum O2 saturation were reviewed and compared. Apnea was defined as 90% decrease TABLE I. Basic Demographic Information. N 5 49
Age Sex (male/female) Body mass index
Demographics
47.9 6 11.7 38 (77.6%)/11 (22.4%) 29.6 6 5.02
Time between pre- and posttreatment polysomnogram
228.7 6 296.5 days
Time between pre–and posttreatment C-reactive protein levels
102.5 6 65.2 days
Laryngoscope 125: July 2015
1734
Samples of peripheral venous blood for CRP evaluation were collected on the day of device fitting and after a minimum of 30 days of treatment with the device during a routine clinic visit. Serum levels of high sensitivity CRP were measured with a latex particle-enhanced immunoturbimetric assay.
Statistical Analysis All statistical analyses were carried out using SPSS for Macintosh Version 12.0 (SPSS, Inc, Chicago, IL). Change in AHI, lowest O2 saturation, and CRP data between baseline polysomnography (PSG) and titration PSG were analyzed with paired t test. Pearson correlation coefficients were computed to evaluate significance and strength between baseline AHI and baseline CRP levels. Data are expressed as mean 6 standard deviation for continuous data and n percent for categorical data. A probability less than 0.05 was accepted as statistically significant.
RESULTS A sample of 49 patients were included in this study. Patients were predominantly male (77.6%), with mean age of 47.9 6 11.7 years and mean BMI of 29.6 6 5.02 kg/ m2 (Table I). Baseline PSG revealed six patients with mild OSAHS, 21 patients with moderate OSAHS, and 22 patients with severe OSAHS. Baseline CRP levels had an average of 2.5 6 1.8 mg/L and did not differ significantly with disease severity. Patients were found to have an overall response to oral appliance treatment with oral appliances. AHI levels were found to decrease in all patient groups. In patients with mild OSAHS, average AHI decreased from 12.9 6 2.4 to 3.3 6 3.8. Average AHI decreased from 20.9 6 3.3 to 6.1 6 7.2 in patients with moderate OSAHS, and decreased from 51.6 6 21.2 to 20.3 6 30.9 in the severe OSAHS group. Mean AHI decreased from 33.7 6 21.8 to 12.1 6 22.3 (95% confidence interval [CI], 16.8 to 26.3) over all levels of severity. Mean lowest nocturnal SaO2 level increased from 85.1% 6 5.9% to 90.7% 6 3.6% (95% CI, 27.1 to 24.1) with use of the oral appliance (Table II). Of the 49 patients, 29 were cured, eight were considered success, and 12 were considered treatment failures (Table III). Similar trends were seen in patient pre- and posttreatment serum C-reactive protein levels. Patients with mild OSAHS had an average CRP level decrease from 2.4 6 2.3 to 1.1 6 1.0. Moderate OSAHS had an average decrease from 2.1 6 1.5 to 1.7 6 1.2. Severe OSAHS had an average decrease from 2.9 6 1.8 to 2.2 6 1.4 (Table Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
TABLE II. Baseline and Titration AHI, Oxygen Saturation, and CRP Levels. Mild
Apnea-Hypopnea Index Baseline PSG Titration PSG P value Lowest O2 %
Moderate
Severe
Overall
12.9 6 2.4
20.9 6 3.3
51.6 6 21.2
33.7 6 21.8
3.3 6 3.8
6.1 6 7.2
20.3 6 30.9
12.1 6 22.3
0.005
0.0001
0.0001
< 0.0001
Baseline
88.7 6 4.2
87.6 6 5.5
81.7 6 4.9
85.1 6 5.9
Titration P value
92.2 6 5.2 0.018
91.7 6 2.3 0.004
89.3 6 3.77 0.0001
90.7 6 3.6 < 0.0001
2.4 6 2.3 1.1 6 1.0
2.1 6 1.5 1.7 6 1.2
2.9 6 1.8 2.2 6 1.4
2.5 6 1.8 1.9 6 1.3
CRP (mg/L) Baseline Titration P value
0.3
0.12
0.048
0.006
AHI 5 Apnea–hypopnea index; CRP 5 C-reactive protein; PSG 5 polysomnography.
II). Overall, the mean baseline CRP level decreased significantly from 2.5 6 1.8 mg/L to 1.9 6 1.3 mg/L (P 5 0.006, 95% CI, 0.2 to 1.1) across all severity levels (Figs. (2 and 3)).
DISCUSSION Systemic inflammation has an established role in the pathogenesis of cardiovascular disease. The American Heart Association specifically recommends using CRP in risk factor assessment in adults without known cardiac disease. A recent meta-analysis by Nadeem et al. showed that patients with OSAHS had statistically significant higher levels of CRP when compared to control individuals.4 Because CRP levels are generally more stable than other cytokines, it is an important marker of systemic inflammation.15 CRP may have a direct role in the pathogenesis of atherosclerosis.16 Elevated CRP levels, even in the high-normal (0.2 to 1.0 mg/dL, normal < 1.0 mg/dL) range in apparently healthy men and women has been shown to increase the relative risk of cardiovascular disease by 1.5, and thus are an important marker to monitor over time.1,2,17–20 Oral appliances are considered an option for firstline therapy for snoring and mild to moderate OSAHS, as well as salvage therapy for severe OSAHS.7 Whereas CPAP has been shown to be more efficacious at reducing AHI; OAs, including MADs, have been shown to have a higher compliance rate, thus resulting in similar long-
term effectiveness.21–24 Many studies have shown that CRP levels decrease with treatment of OSAHS. Baessler et al. published a meta-analysis on 14 studies with 771 patients, showing that CPAP therapy significantly decreased levels of inflammatory markers.25 CRP levels have also been found to decrease following surgical treatment of OSAHS.9 However, thus far no studies have been done correlating oral appliances with changes in CRP levels. The results of this study indicate that treatment of OSAHS with MADs significantly reduced AHI and improved oxygen saturation across all severities of disease. It was found that approximately 80% of patients achieved successful or curative response to treatment, and a majority reported cessation of clinical symptoms. Furthermore, CRP levels were reduced significantly across the entire patient population. However, subgroup analysis found that, although CRP levels did decrease with treatment, some changes in levels were not statistically significant. Similarly, the difference in baseline CRP levels between mild, moderate, and severe OSAHS groups was not significant. These findings are likely due
TABLE III. Outcomes of Oral Appliance Treatment. Cure
Success
Failure
Mild (AHI 5–15)
4
0
2
Moderate (AHI 15–30) Severe (AHI 30)
15 10
2 6
4 6
Overall
29
8
12
AHI 5 Apnea–Hypopnea index.
Laryngoscope 125: July 2015
Fig. 2. Average pre- and posttreatment CRP levels. CRP 5 C-reactive protein. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
1735
Fig. 3. Patient baseline and posttreatment CRP Levels (N 5 49). CRP 5 C-reactive protein. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
to the small sample size in each subgroup, which is a notable limitation to the study. Although posttreatment CRP levels were recommended as part of the protocol for all patients fitted with MADs, there was a notable loss to follow-up and failure of many patients to obtain a repeat CRP level. Another limitation of the study includes the short follow-up period. Several studies have found that treatment adherence with oral appliances decreases over time.26 However, our ability to study adherence and subsequent long-term decreases in CRP over time was limited. Further studies can be done to assess effect of oral appliances on CRP in long-term treatment.
CONCLUSION The association of inflammatory mediators such as C-reactive protein with OSAHS and subsequent reduction of CRP levels with treatment has been well documented for CPAP and surgery. We suggest that CRP levels will also decrease in treatment of OSAHS with oral appliances, which is a reasonable and noninvasive approach to treatment for patients who refuse or fail CPAP therapy.
BIBLIOGRAPHY 1. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and Interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–1134.
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2. Shamsuzzaman A, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105: 2462–2464. 3. Kortuk O, Ciftci T, Mollarecep E, et al. Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome. Intl Heart Journal 2005;46:801–809. 4. Nadeem R, Molnar J, Madbouly E, et al. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med 2013;9:1003– 1012. 5. Fanfulla F, Grassi M, Taurino A, et al. The relationship of daytime hypoxemia and nocturnal hypoxia in obstructive sleep apnea syndrome. Sleep 2008;31:249–255. 6. Peled N, Greenberg A, Pillar G, et al. Contributions of hypoxia and respiratory disturbance index to sympathetic activation and blood pressure in obstructive sleep apnea syndrome. Am J Hypertension 1998;11:1284– 1289. 7. Kushida C, Morgenthaler T, Littner M, et al. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240–243. 8. Friedman M, Samuelson C, Hamilton C. Effect of continuous positive airway pressure on C-reactive protein levels in sleep apnea: a meta-analysis. Otolaryngol Head Neck Surg 2012;147:423–433. 9. Friedman M, Bliznikas D, Vidyasagar R, Woodson T, Joseph N. Reduction of C-reactive protein with surgical treatment of obstructive sleep apnea hypopnea syndrome. Otolaryngol Head Neck Surg 2006;135:900–905. 10. Patruno V, Aiolfi S, Costantino G, et al. Fixed and autoadjusting continuous positive airway pressure treatments are not similar in reducing cardiovascular risk factors in patients with obstructive sleep apnea. Chest 2007;10:1393–1399. 11. Schiza S, Bouloukaki I, Mermigkis C, et al. C-reactive protein evolution in obstructive sleep apnoea patients under CPAP therapy. Eur J Clin Invest 2010;10:968–975. 12. Iesato K, Tatsumi K, Saibara T, et al. Decreased lipoprotein lipase in obstructive sleep apnea syndrome. Circulation 2007;10:1293–1298. 13. Ishida K, Kato M, Kato Y, et al. Appropriate use of nasal continuous positive airway pressure decreases elevated C-reactive protein in patients with obstructive sleep apnea. Chest 2009;10:125–129. 14. Ryan S, Nolan G, Hannigan E, et al. Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation witho besity. Thorax 2007;10:509–514. 15. Jialal I, Devaraj S, Venugopal S, et al. C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension 2004;10:6–11. 16. Calabro P, Willerson J, Yeh E, et al. Inflammatory cytokines stimulated Creactive protein production by human coronary artery smooth muscle cells. Circulation 2003;10:1930–1932. 17. Ridker P. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103:1813–1818. 18. Bhushan B, Guleria R, Misra A, et al. Obstructive sleep apnoea correlates with C-reactive protein in obese Asian Indians. Nutr Metab Cardiovasc Dis 2009;19:184–189. 19. Drager L, Lopes H, Maki-Nunes C, et al. The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. PLoS One 2010;5:e12065. doi: 10.1371/ journal.pone.0012065. 20. Lin H, Friedman M, Chang H, et al. The efficacy of multilevel surgery of the upper airway in adults with obstructive sleep apnea-hypopnea syndrome. Laryngoscope 2008;118:902–908. 21. Phillips C, Grunstein R, Darendeliler M, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea. Am J Respiratory Critical Care Med 2013;187: 879–887. 22. Doff M, Hoekema A, Wijkstra P, et al. Oral appliance versus continuous positive airway pressure in obstructive sleep apnea syndrome. Sleep 2013;36:1289–1296. 23. Guven S, Turkkani M, Ciftci B, et al. The relationship between highsensitivity C-reactive protein levels and the severity of obstructive sleep apnea. Sleep Breath 2012;16:217–221. 24. Ferguson K, Cartwright R, Rogers R, et al. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2006;29:244–262. 25. Baessler A, Nadeem R, Harvey M, et al. Treatment for sleep apnea by continuous positive airway pressure improves levels of inflammatory markers-a meta-analysis. J Inflamm 2013;10:13. 26. Walker-Engstrom M, Tegelberg A, et al. 4-year follow-up of treatment with dental appliance or uvulopalatopharyngoplasty in pateints with obstructive sleep apnea: a randomized study. Chest 2002;121:739–746.
Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
Rhinological and Otological Society, Inc.
Impact of Mandibular Advancement Devices on C-reactive Protein Levels in Patients With Obstructive Sleep Apnea Sreeya Yalamanchali, MD; Anna M. Salapatas, BS; Michelle S. Hwang, BS; Thomas R. Pott, MD; Mary E. Lundgren, PhD; Ninos J. Joseph, BS; Michael Friedman, MD Objectives/Hypothesis: To determine the effect of treatment of obstructive sleep apnea (OSA) with custom-made mandibular advancement devices (MADs) on C-reactive protein (CRP) levels in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). Study Design: Case series with chart review. Methods: Charts of consecutive patients fitted with custom-made mandibular advancement devices for treatment of OSAHS between December 2011 and November 2012 were reviewed. Demographics such as age, sex, and body mass index (BMI) were collected. Prefitting and postfitting polysomnograms were reviewed. Pre- and posttreatment apnea–hypopnea index (AHI) and average O2 saturation were compared. Only patients with documented CRP levels determined prior to mandibular advancement device fitting and again after improvement of OSAHS symptoms were included. Results: Forty-nine patients (77.6% male, age 47.4 6 11.7 years, BMI 29.6 6 5.0 kg/m2) were included in this study. Patients initially had elevated CRP levels (2.5 6 1.8 mg/dl), which decreased significantly following use of their custom-made mandibular advancement device (1.9 6 1.3 mg/dl, P 5 0.006) by approximately 24%. AHI decreased significantly from 33.3 6 21.7 pretreatment to 12.1 6 22.3 posttreatment (P < 0.001). Treatment with MADs reduced AHI by approximately 69.3%. Minimum oxygen saturation significantly improved from 85.1% 6 5.9 pretreatment to 90.7% 6 3.6 posttreatment (P < 0.001). Conclusion: Treatment with custom-made mandibular advancement devices significantly reduced elevated CRP levels in patients with mild to severe OSAHS. Therapy achieves reasonable response and cure rates in the observed patients with a significant reduction in AHI. Key Words: Oral appliances, mandibular advancement devices, obstructive sleep apnea, C-reactive protein. Level of Evidence: 4. Laryngoscope, 125:1733–1736, 2015
INTRODUCTION Multiple epidemiological studies have shown a strong link between systemic inflammation and obstructive sleep apnea-hypopnea syndrome (OSAHS).1–4 Repetitive hypoxemic stress from apneic and/or hypopneic episodes results in sympathetic activation, which causes persistent hypertension and increased levels of systemic inflammatory mediators including intercellular adhesion molecules, coagulation factors, and C-reactive protein (CRP).1–6
From the Rush University Medical Center (M.F.); and the Advanced Center for Specialty Care, Advocate Illinois Masonic Medical Center (S.Y., A.M.S., M.S.H., T.R.P., M.E.L., N.J.J., M.F.), Chicago, Illinois, U.S.A. Editor’s Note: This Manuscript was accepted for publication November 6, 2014. Presented as a poster at the 2013 Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Vancouver, British Columbia, Canada, September 29–October 2, 2013. Michael Friedman is the recipient of a research grant from Imthera Medical (San Diego, CA) to conduct a clinical research trial. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Conflict of Interest: None. Send correspondence to Michael Friedman, MD, FACS, Chicago ENT, 30 North Michigan Ave, Suite 1107, Chicago, Illinois 60602. Email: [email protected]
In 2006, the American Academy of Sleep Medicine (AASM) changed their recommendations to include oral appliances (OAs) as first-line therapy for snoring and mild to moderate OSAHS and as salvage therapy for severe OSAHS.7 Oral appliances range from custommade titratable to nontitratable thermoplastic mandibular advancement devices (MADs). Many prior studies have noted a statistically significant decrease in CRP levels after continuous positive airway pressure (CPAP) or surgical treatment of patients with OSAHS,8–14 but thus far no studies have looked at the effect of oral appliances on CRP levels in patients with OSAHS. The objective of this study was to determine the effect of treatment with a custom-made, titratable oral appliance device on serum C-reactive protein levels in patients diagnosed with OSAHS.
MATERIALS AND METHODS Patient Selection
DOI: 10.1002/lary.25061
Approval for this retrospective study was obtained from the Western Institutional Review Board (Puyallup, WA). Charts of 330 consecutive patients diagnosed with OSA and fitted with a custom-made oral appliance device between December 2011 and November 2012 were identified. Patients included in this study either failed CPAP therapy or chose a custom-made MAD
Laryngoscope 125: July 2015
Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
1733
in airflow for 10 seconds relative to basal amplitude. Hypopnea was defined as 50% decrease in the airflow amplitude relative to baseline value, lasting for 10 seconds with the presence of arousal or oxygen desaturation of at least 4%. Patients with AHI 5 to 15 were considered to have mild OSAHS; patients with AHI 15 to 30 were considered to have moderate OSAHS; and patients with AHI 30 were considered to have severe OSAHS (AASM criteria). After treatment, patients were classified using the categories cure, success, or failure. Cure was defined as posttreatment AHI 5. Success was defined as a reduction in AHI of 50% or more and an AHI 20.
Measurement of C-Reactive Protein Fig. 1. TAP 3: Custom-made titratable oral appliance. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] as their primary treatment option. All patients diagnosed with OSAHS, regardless of type of intervention, undergo CRP monitoring at the time of diagnosis. Although CRP testing is recommended in all patients in posttreatment follow-up, there is a high rate of noncompliance for additional CRP testing. Fortynine patients had data available on a baseline polysomnogram (PSG) and a titration PSG with their device, and they completed a blood draw for a CRP level on the day of fitting and after a minimum of 30 days of treatment with their device. Patients with an initial CRP level >10 were excluded. Demographic information including age, sex, and body mass index (BMI) was collected.
Mandibular Advancement Device Fitting All patients were fitted with the Thorton Adjustable Positioner 3 (TAP 3; Airway Management, Inc., Dallas, TX) by a doctor of dental medicine. The TAP 3 is a custom-made, two-piece appliance that fits over the upper and lower teeth (Fig. 1). Alginate impressions of upper and lower dental arches were recorded and poured in dental stone and sent to the dental arts laboratory. Once the custom-made TAP 3 was ready, patients were refitted with the oral appliance to ensure a comfortable fit. The TAP 3 has an anterior dial that allows for adjustment of the device to achieve maximum comfort and efficacy. Each turn is equal to 0.25 mm of additional jaw protrusion.
Polysomnography All patients had a reported 1-night, baseline formal laboratory polysomnographic evaluation and a follow-up titration study with their custom-made device in the same sleep lab. Apnea–hypopnea index (AHI) and minimum O2 saturation were reviewed and compared. Apnea was defined as 90% decrease TABLE I. Basic Demographic Information. N 5 49
Age Sex (male/female) Body mass index
Demographics
47.9 6 11.7 38 (77.6%)/11 (22.4%) 29.6 6 5.02
Time between pre- and posttreatment polysomnogram
228.7 6 296.5 days
Time between pre–and posttreatment C-reactive protein levels
102.5 6 65.2 days
Laryngoscope 125: July 2015
1734
Samples of peripheral venous blood for CRP evaluation were collected on the day of device fitting and after a minimum of 30 days of treatment with the device during a routine clinic visit. Serum levels of high sensitivity CRP were measured with a latex particle-enhanced immunoturbimetric assay.
Statistical Analysis All statistical analyses were carried out using SPSS for Macintosh Version 12.0 (SPSS, Inc, Chicago, IL). Change in AHI, lowest O2 saturation, and CRP data between baseline polysomnography (PSG) and titration PSG were analyzed with paired t test. Pearson correlation coefficients were computed to evaluate significance and strength between baseline AHI and baseline CRP levels. Data are expressed as mean 6 standard deviation for continuous data and n percent for categorical data. A probability less than 0.05 was accepted as statistically significant.
RESULTS A sample of 49 patients were included in this study. Patients were predominantly male (77.6%), with mean age of 47.9 6 11.7 years and mean BMI of 29.6 6 5.02 kg/ m2 (Table I). Baseline PSG revealed six patients with mild OSAHS, 21 patients with moderate OSAHS, and 22 patients with severe OSAHS. Baseline CRP levels had an average of 2.5 6 1.8 mg/L and did not differ significantly with disease severity. Patients were found to have an overall response to oral appliance treatment with oral appliances. AHI levels were found to decrease in all patient groups. In patients with mild OSAHS, average AHI decreased from 12.9 6 2.4 to 3.3 6 3.8. Average AHI decreased from 20.9 6 3.3 to 6.1 6 7.2 in patients with moderate OSAHS, and decreased from 51.6 6 21.2 to 20.3 6 30.9 in the severe OSAHS group. Mean AHI decreased from 33.7 6 21.8 to 12.1 6 22.3 (95% confidence interval [CI], 16.8 to 26.3) over all levels of severity. Mean lowest nocturnal SaO2 level increased from 85.1% 6 5.9% to 90.7% 6 3.6% (95% CI, 27.1 to 24.1) with use of the oral appliance (Table II). Of the 49 patients, 29 were cured, eight were considered success, and 12 were considered treatment failures (Table III). Similar trends were seen in patient pre- and posttreatment serum C-reactive protein levels. Patients with mild OSAHS had an average CRP level decrease from 2.4 6 2.3 to 1.1 6 1.0. Moderate OSAHS had an average decrease from 2.1 6 1.5 to 1.7 6 1.2. Severe OSAHS had an average decrease from 2.9 6 1.8 to 2.2 6 1.4 (Table Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
TABLE II. Baseline and Titration AHI, Oxygen Saturation, and CRP Levels. Mild
Apnea-Hypopnea Index Baseline PSG Titration PSG P value Lowest O2 %
Moderate
Severe
Overall
12.9 6 2.4
20.9 6 3.3
51.6 6 21.2
33.7 6 21.8
3.3 6 3.8
6.1 6 7.2
20.3 6 30.9
12.1 6 22.3
0.005
0.0001
0.0001
< 0.0001
Baseline
88.7 6 4.2
87.6 6 5.5
81.7 6 4.9
85.1 6 5.9
Titration P value
92.2 6 5.2 0.018
91.7 6 2.3 0.004
89.3 6 3.77 0.0001
90.7 6 3.6 < 0.0001
2.4 6 2.3 1.1 6 1.0
2.1 6 1.5 1.7 6 1.2
2.9 6 1.8 2.2 6 1.4
2.5 6 1.8 1.9 6 1.3
CRP (mg/L) Baseline Titration P value
0.3
0.12
0.048
0.006
AHI 5 Apnea–hypopnea index; CRP 5 C-reactive protein; PSG 5 polysomnography.
II). Overall, the mean baseline CRP level decreased significantly from 2.5 6 1.8 mg/L to 1.9 6 1.3 mg/L (P 5 0.006, 95% CI, 0.2 to 1.1) across all severity levels (Figs. (2 and 3)).
DISCUSSION Systemic inflammation has an established role in the pathogenesis of cardiovascular disease. The American Heart Association specifically recommends using CRP in risk factor assessment in adults without known cardiac disease. A recent meta-analysis by Nadeem et al. showed that patients with OSAHS had statistically significant higher levels of CRP when compared to control individuals.4 Because CRP levels are generally more stable than other cytokines, it is an important marker of systemic inflammation.15 CRP may have a direct role in the pathogenesis of atherosclerosis.16 Elevated CRP levels, even in the high-normal (0.2 to 1.0 mg/dL, normal < 1.0 mg/dL) range in apparently healthy men and women has been shown to increase the relative risk of cardiovascular disease by 1.5, and thus are an important marker to monitor over time.1,2,17–20 Oral appliances are considered an option for firstline therapy for snoring and mild to moderate OSAHS, as well as salvage therapy for severe OSAHS.7 Whereas CPAP has been shown to be more efficacious at reducing AHI; OAs, including MADs, have been shown to have a higher compliance rate, thus resulting in similar long-
term effectiveness.21–24 Many studies have shown that CRP levels decrease with treatment of OSAHS. Baessler et al. published a meta-analysis on 14 studies with 771 patients, showing that CPAP therapy significantly decreased levels of inflammatory markers.25 CRP levels have also been found to decrease following surgical treatment of OSAHS.9 However, thus far no studies have been done correlating oral appliances with changes in CRP levels. The results of this study indicate that treatment of OSAHS with MADs significantly reduced AHI and improved oxygen saturation across all severities of disease. It was found that approximately 80% of patients achieved successful or curative response to treatment, and a majority reported cessation of clinical symptoms. Furthermore, CRP levels were reduced significantly across the entire patient population. However, subgroup analysis found that, although CRP levels did decrease with treatment, some changes in levels were not statistically significant. Similarly, the difference in baseline CRP levels between mild, moderate, and severe OSAHS groups was not significant. These findings are likely due
TABLE III. Outcomes of Oral Appliance Treatment. Cure
Success
Failure
Mild (AHI 5–15)
4
0
2
Moderate (AHI 15–30) Severe (AHI 30)
15 10
2 6
4 6
Overall
29
8
12
AHI 5 Apnea–Hypopnea index.
Laryngoscope 125: July 2015
Fig. 2. Average pre- and posttreatment CRP levels. CRP 5 C-reactive protein. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
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Fig. 3. Patient baseline and posttreatment CRP Levels (N 5 49). CRP 5 C-reactive protein. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
to the small sample size in each subgroup, which is a notable limitation to the study. Although posttreatment CRP levels were recommended as part of the protocol for all patients fitted with MADs, there was a notable loss to follow-up and failure of many patients to obtain a repeat CRP level. Another limitation of the study includes the short follow-up period. Several studies have found that treatment adherence with oral appliances decreases over time.26 However, our ability to study adherence and subsequent long-term decreases in CRP over time was limited. Further studies can be done to assess effect of oral appliances on CRP in long-term treatment.
CONCLUSION The association of inflammatory mediators such as C-reactive protein with OSAHS and subsequent reduction of CRP levels with treatment has been well documented for CPAP and surgery. We suggest that CRP levels will also decrease in treatment of OSAHS with oral appliances, which is a reasonable and noninvasive approach to treatment for patients who refuse or fail CPAP therapy.
BIBLIOGRAPHY 1. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and Interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–1134.
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2. Shamsuzzaman A, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105: 2462–2464. 3. Kortuk O, Ciftci T, Mollarecep E, et al. Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome. Intl Heart Journal 2005;46:801–809. 4. Nadeem R, Molnar J, Madbouly E, et al. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med 2013;9:1003– 1012. 5. Fanfulla F, Grassi M, Taurino A, et al. The relationship of daytime hypoxemia and nocturnal hypoxia in obstructive sleep apnea syndrome. Sleep 2008;31:249–255. 6. Peled N, Greenberg A, Pillar G, et al. Contributions of hypoxia and respiratory disturbance index to sympathetic activation and blood pressure in obstructive sleep apnea syndrome. Am J Hypertension 1998;11:1284– 1289. 7. Kushida C, Morgenthaler T, Littner M, et al. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240–243. 8. Friedman M, Samuelson C, Hamilton C. Effect of continuous positive airway pressure on C-reactive protein levels in sleep apnea: a meta-analysis. Otolaryngol Head Neck Surg 2012;147:423–433. 9. Friedman M, Bliznikas D, Vidyasagar R, Woodson T, Joseph N. Reduction of C-reactive protein with surgical treatment of obstructive sleep apnea hypopnea syndrome. Otolaryngol Head Neck Surg 2006;135:900–905. 10. Patruno V, Aiolfi S, Costantino G, et al. Fixed and autoadjusting continuous positive airway pressure treatments are not similar in reducing cardiovascular risk factors in patients with obstructive sleep apnea. Chest 2007;10:1393–1399. 11. Schiza S, Bouloukaki I, Mermigkis C, et al. C-reactive protein evolution in obstructive sleep apnoea patients under CPAP therapy. Eur J Clin Invest 2010;10:968–975. 12. Iesato K, Tatsumi K, Saibara T, et al. Decreased lipoprotein lipase in obstructive sleep apnea syndrome. Circulation 2007;10:1293–1298. 13. Ishida K, Kato M, Kato Y, et al. Appropriate use of nasal continuous positive airway pressure decreases elevated C-reactive protein in patients with obstructive sleep apnea. Chest 2009;10:125–129. 14. Ryan S, Nolan G, Hannigan E, et al. Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation witho besity. Thorax 2007;10:509–514. 15. Jialal I, Devaraj S, Venugopal S, et al. C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension 2004;10:6–11. 16. Calabro P, Willerson J, Yeh E, et al. Inflammatory cytokines stimulated Creactive protein production by human coronary artery smooth muscle cells. Circulation 2003;10:1930–1932. 17. Ridker P. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103:1813–1818. 18. Bhushan B, Guleria R, Misra A, et al. Obstructive sleep apnoea correlates with C-reactive protein in obese Asian Indians. Nutr Metab Cardiovasc Dis 2009;19:184–189. 19. Drager L, Lopes H, Maki-Nunes C, et al. The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. PLoS One 2010;5:e12065. doi: 10.1371/ journal.pone.0012065. 20. Lin H, Friedman M, Chang H, et al. The efficacy of multilevel surgery of the upper airway in adults with obstructive sleep apnea-hypopnea syndrome. Laryngoscope 2008;118:902–908. 21. Phillips C, Grunstein R, Darendeliler M, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea. Am J Respiratory Critical Care Med 2013;187: 879–887. 22. Doff M, Hoekema A, Wijkstra P, et al. Oral appliance versus continuous positive airway pressure in obstructive sleep apnea syndrome. Sleep 2013;36:1289–1296. 23. Guven S, Turkkani M, Ciftci B, et al. The relationship between highsensitivity C-reactive protein levels and the severity of obstructive sleep apnea. Sleep Breath 2012;16:217–221. 24. Ferguson K, Cartwright R, Rogers R, et al. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2006;29:244–262. 25. Baessler A, Nadeem R, Harvey M, et al. Treatment for sleep apnea by continuous positive airway pressure improves levels of inflammatory markers-a meta-analysis. J Inflamm 2013;10:13. 26. Walker-Engstrom M, Tegelberg A, et al. 4-year follow-up of treatment with dental appliance or uvulopalatopharyngoplasty in pateints with obstructive sleep apnea: a randomized study. Chest 2002;121:739–746.
Yalamanchali et al.: Impact of MADs on CRP Levels in OSA
