THERE IS NOW FIRM EPIDEMIOLOGICAL EVIDENCE THAT THE OBSTRUCTIVE SLEEP APNEA/HYPOPNEA SYNDROME (OSAHS) IS ASSOCIATED WITH HYPERTENSION INDEPENDENT OF CONFOUNDERS SUCH AS OBESITY, CENTRAL OBESITY, GENDER, MIDDLE AGE, ALCOHOL, SMOKING AND CAFFEINE IN NORMAL,1-3 SLEEP APNOEA4,5 AND HYPERTENSIVE6 POPULATIONS.

This is supported by a case-control study7 demonstrating that 24 hour blood pressure was 4 to 5 mmHg higher in OSAHS patients compared to carefully matched controls, with the greatest differences occurring during the night. Data from animal studies show that intermittent apneas8 or hypoxemia8,9 during sleep increase 24 hour blood pressure. In animal models, this is at least partly due to increased sympathetic tone9 which is also found in patients with SAHS10 and is reduced by CPAP therapy.11,12 Randomized controlled studies have shown that CPAP can reduce blood pressure in patients with OSAHS13-15 and this issue of the journal contains the first randomized controlled trial indicating that oral appliances may also reduce blood pressure in OSAHS.16 There is a need thus to try to clarify which therapy should be used in which patients in terms of efficacy in treating blood pressure.

The reduction in blood pressure produced by CPAP therapy varies markedly between studies. In the first randomized placebo controlled study by Faccenda and colleagues, there was a small but significant mean reduction in 24 hour diastolic blood pressure of 1.4 mmHg across all patients with the greatest falls between 2 am and 10 am, and no significant change in systolic pressure.13 However, the falls in blood pressure were greater in two groups selected "a priori", those using CPAP more than 3.5 hrs/night having diastolic decreases of 1.9 mmHg and those with more than twenty 4% desaturations/hr having decreases of 5 mmHg in diastolic and 4 mmHg systolic pressure.13 A parallel group study by Pepperell and colleagues showed a decrease in mean arterial pressure of 3 mmHg, with a larger drop of 5 mmHg in those with more than thirty three 4% desaturations/hr.15 A third study by Becker and colleagues found a greater fall in mean blood pressure of 9.9 mmHg.14 The different magnitudes of drop in blood pressure need explanation. Possible reasons include differences in the extent of transient hypoxemia during sleep. Firstly, the patient groups were different with less severe OSAHS and particularly less severe nocturnal hypoxemia in Faccenda's study which showed least change in blood pressure.13 In that study, there was no requirement for hypoxemia either as a direct entry criterion or in the definition of hypopneas and the median number of 4% desaturations was 7/hr. In contrast, the entry criterion for Pepperell's study15 was more than ten 4% desaturations/hr and in Becker's study,14 the mean minimum saturation was 63sd 15% indicating very severe desaturation. Other potential differences include differences in patient supervision throughout the study period in Becker's trial14 and the fact that only 53% of Becker's patients completed the trial opening the possibility of selection bias towards responders and users.

Gotsopoulos' well designed study in this issue reports that oral appliances result in a decrease in mean 24 hour diastolic blood pressure of 1.8 mmHg16 in patients with OSAHS. These results add significantly to the randomized controlled studies carried out by the same group showing improved sleep and breathing during sleep17 and improved symptoms18 with oral devices. Two unexpected results in the current study were the failure to show any drop in blood pressure during sleep, a consistent finding in the CPAP studies, and the lack of relationship between oxygenation and blood pressure change across the patients. Both may reflect sample size, but in comparison to the CPAP studies this study was better,14 or as well powered.13,15 How would this compare with the effect of CPAP on similar patients? The entry criteria16 included an AHI of more than 10 with hypopneas requiring accompanying 3% desaturation or arousal, and overall the patients had a mean AHI of 27sd15 and a lowest oxygen saturation of 85%. Gotsopoulos' patients were probably similar to those in Faccenda's study (Faccenda's patients median AHI 35 with no desaturation or arousal requirement and median lowest oxygen saturation of 88%), and were probably milder than those in the Pepperell study. Thus, the reported reduction in blood pressure with the oral appliance may be similar to that expected with CPAP in similar patients, although direct comparative studies are needed. Also required are studies to determine whether either therapy results in significant decreases in blood pressure compared to placebo in the very large number of individuals who have many apneas and hypopneas during sleep but are not sleepy. All 4 studies13-16 showing significant falls in blood pressure with treatment have been in sleepy patients with OSAHS, the only investigation in asymptomatic individuals with OSAH showed no significant fall in blood pressure with CPAP.19

Both CPAP and oral appliances are obtrusive and sometimes uncomfortable treatments and ensuring continued patient use can be difficult. The extent of this problem is well documented with CPAP20 but unclear with oral appliances. All existing data on oral appliance use are based on self reports with only partial follow up, and self reports of use are known to be over optimistic at least for CPAP,21 and there is a real need for objective data on appliance use. Some studies have indicated that no more than 50% of those prescribed oral appliances used them long-term22 but used fairly basic oral appliances and data are urgently required on usage of more sophisticated oral appliances. Direct comparisons of oral devices and CPAP in terms of symptoms and vigilance are few and conflicting,23,24 although the largest indicated that benefits were greater with CPAP,24 although again basic oral appliances were used. Cistulli's groups work16-18 challenges the field to do well designed and well powered studies comparing the effects of state of the art CPAP against state of the art oral appliances on long term outcomes including blood pressure in OSAHS patients. Until these are done, the conservative position is to regard CPAP as the treatment of choice for OSAHS, but the fact that oral appliances have now been shown to improve blood pressure further strengthens their position to be the second line therapy of choice.

References

1. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Leiby BE, Vela-Bueno A, et al. Association of hypertension and sleep-disordered breathing. Arch Intern Med 2000; 160:2289-2295.

2. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-disordered breathing, obstructive sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000; 283:1829-1836.

3. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384.

4. Grote L, Ploch T, Heitmann J, Knaack L, Penzel T, Peter JH. Sleep-related breathing disorder is an independent risk factor for systemic hypertension. Am J Respir Crit Care Med 1999; 160:1875-1882.

5. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000; 320:479-482.

6. Worsnop CJ, Naughton MT, Barter CE, Morgan TO, Anderson AI, Pierce RJ. The prevalence of obstructive sleep apnea in hypertensives. Am J Respir Crit Care Med 1998; 157:111-115.

7. Davies CW, Crosby JH, Mullins RL, Barbour C, Davies RJ, Stradling JR. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax 2000; 55:736-740.

8. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997; 99:106-109.

9. Lesske J, Fletcher EC, Bao G, Unger T. Hypertension caused by chronic intermittent hypoxia—influence of chemoreceptors and sympathetic nervous system. J Hypertens 1997; 15:1593-1603.

10. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897-1904.

11. Waradekar NV, Sinoway LI, Zwillich CW, Leuenberger UA. Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med 1996; 153:1333-1338.

12. Heitmann J, Ehlenz K, Penzel T, Becker HF, Grote L, Voigt KH et al. Sympathetic activity is reduced by nCPAP in hypertensive obstructive sleep apnoea patients. Eur Respir J 2004; 23:255-262.

13. Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized Placebo-controlled Trial of Continuous Positive Airway Pressure on Blood Pressure in the Sleep Apnea-Hypopnea Syndrome. Am J Respir Crit Care Med 2001; 163:344-348.

14. Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003; 107:68-73.

15. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359:204-210.

16. Gotsopoulos H; Kelly JJ; Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. SLEEP 2004;27(5):934-41.

17. Mehta A, Qian J, Petocz P, Darendeliler MA, Cistulli PA. A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med 2001; 163:1457-1461.

18. Gotsopoulos H, Chen C, Qian J, Cistulli PA. Oral appliance therapy improves symptoms in obstructive sleep apnea: a randomized, controlled trial. Am J Respir Crit Care Med 2002; 166:743-748.

19. Barbe F, Mayoralas LR, Duran J, Masa JF, Maimo A, Montserrat JM et al. Treatment with continuous positive airway pressure is not effective in patients with obstructive sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern.Med 2001; 134:1015-1023.

20. McArdle N, Devereux G, Heidarnejad H, Engleman HM, Mackay TW, Douglas NJ. Long-term use of CPAP therapy for obstructive sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159:1108-1114.

21. Engleman HM, Asgari-Jirhandeh N, McLeod AL, Ramsay CF, Deary IJ, Douglas NJ. Self-reported use of CPAP and benefits of CPAP therapy: a patient survey. Chest 1996; 109:1470-1476.

22. McGown AD, Makker HK, Battagel JM, L’Estrange PR, Grant HR, Spiro SG. Long-term use of mandibular advancement splints for snoring and obstructive sleep apnoea: a questionnaire survey. Eur Respir J 2001; 17:462-466.

23. Ferguson KA, Ono T, Lowe AA, Keenan SP, Fleetham JA. A randomized crossover study of an oral appliance vs nasal- continuous positive airway pressure in the treatment of mild- moderate obstructive sleep apnea. Chest 1996; 109:1269-1275.

24. Engleman HM, McDonald JP, Graham D, Lello GE, Kingshott RN, Coleman EL, et al. Randomized crossover trial of two treatments for obstructive sleep apnea/hypopnea syndrome: continuous positive airway pressure and mandibular repositioning splint. Am J Respir Crit Care Med 2002; 165:855-859.

Disclosure Statement

Dr. Douglas is a Consultant for ResMed, Ltd., in an advisory capacity only.

Address correspondence to: Neil J. Douglas, MD, DSc, PRCPE, Respiratory Medicine, Room S1643 (2nd Floor), Royal Infirmary, 51 Little France Crescent, Edinburgh, Scotland EH16 4SA, UNITED KINGDOM, Ph: +44-131-242-1836, Fax: +44-131-242-1776, e-mail: n.j.douglas@ed.ac.uk

SLEEP, Vol. 27, No. 5, 2004 842