Pathology and Treatment of OSA

OSA etiology in adults elicits increased upper airway resistance and airway closure caused by anatomic factors (Schellenberg et al., 2000; Kao et al., 2003; Schwab et al., 2003) and physiological factors that induce dysfunction of airway-dilating muscles and collapsibility of airway (Lindman and Stal, 2002; Mortimore and Douglas, 1997). The former includes pathological factors occurred in nose, tongue, lateral pharyngeal walls, soft palate, tonsils, and parapharyngeal fat pads, whereas the latter is mainly caused by reduced reflex responses of tongue and soft palate muscles to negative airway pressure (Fleisher and Krieger, 2007).

OSA is highly associated with insulin resistance and metabolic syndrome for adults. It was found that visceral fat accumulation, a marker of insulin resistance, rather than subcutaneous adiposity is strongly associated with OSA (Shinohara et al., 1997). In addition, adults who snore are more likely to develop type II diabetes mellitus and cardiovascular diseases (Al-Delaimy et al., 2002). It was also found that insulin resistance in obese children is associated with OSA and short sleep duration (Flint et al., 2007; De La Eva et al., 2002). However, compared to adults, pediatric OSA is usually caused by adenotonsillar hypertrophy (Guilleminault et al., 2005; Brouillette et al., 2000).

OSA is a risk factor for cardiovascular morbidities (Luthje and Andreas, 2007; Shahar et al., 2001; Peppard et al., 2000) including hypertension, pulmonary hypertension (Schultz et al., 2005; Atwood et al., 2004), atrial fibrillation (Gami et al., 2004), left ventricular diastolic dysfunction (Arias et al., 2005), myocardial infarction, heart failure (Bradley and Floras 2003), stroke (Yaggi et al., 2005), and sudden death (Gami et al., 2005). Autonomous imbalance such as elevated sympathetic activation for OSA patients is manifested with higher heart rates, less heart rate variability, and higher blood pressure than normal control subjects (Caples et al., 2005). Sympathetic activation was also identified

to have connection with impaired glucose tolerance and leptin resistance, which might explain that patients with OSA have higher fasting blood glucose level and greater risk in developing diabetes mellitus (Luthje and Andreas, 2007). Endothelial dysfunction is a precursor of arterial hypertension and has been reported to increase cardiovascular diseases (see Luthje and Andreas 2007 for review). Impairment of endothelial function has been observed in OSA patients with abnormally increased levels of endothelin-1 (Gjorup et al., 2007; Grebe et al., 2006; Nieto et al..

2004; Phillips et al., 1999) which in turn induce hypertension and related cardiovascular disease.

Local disruption in the regulation of sleep in frontal lobes caused by apnea inducing hypoxia and hypercapnias was proposed (Huupponen et al., 2006). The pathology finding is manifested by inter-hemispheric spindle frequency difference in apnea patients. Spindles can be detected and observed by EEG with a mean duration of 1 second which originate from thalamus and then propagate to the cerebral cortex. Spindles are considered to be the events for maintaining sleep by blocking the transfer of sensory signals to the cerebral cortex during sleep (Jankel and Niedermeyer, 1985; Steriade, 1992).

1-5-2 Treatment of OSA

Continuous positive airway pressure (CPAP) is deemed as the most effective technique and is generally used as a tool for treating patients with OSA (Basner, 2007). In addition to having the effect in enlarging the airway by changing the dimension of the lateral pharyngeal walls (Schwab et al., 1996), it also increases the tone of the upper airway dilator muscles by reducing susceptibility to collapse (Mortimore and Douglas, 1997). Standard CPAP has constant inspiratory and expiratory pressures, while automated CPAP (APAP) is able to continuously adjust

pressure in providing better efficiency and compliance compared to CPAP titration (Masa et al., 2004). El Solh et al. (2007) used a general regression neural network (GRNN) to develop a predictive model for determination of optimal CPAP titration pressure, Pprep(ANN), which contrasts to traditional regression equation that the optimal CPAP pressure was calculated from the following equation:

Pprep(RE)=(0.16xNC)+(0.13xBMI)+(0.04xAHI)-5.12

In order to obtain real optimal pressure for comparison with Pprep(ANN) and Pprep(RE), the initial pressure of CPAP was set at a pressure of 4 cm H2O and was gradually increased by 1 cm H2O for every 20 minutes until the level that apnea, hypopnea, snoring, and recurrent oxyhemoglobin desaturation rather than arousal are eliminated. The optimal pressure, P_opt, was defined as the lowest pressure when the patient has an AHI<5 (El Solh et al., 2007). The results indicated that the correlation between Popt

and Pprep(ANN) was higher than the correlation between Popt and Pprep(RE) (El Solh et al., 2007).

Treatment of OSA patients with CPAP was reported to have significant improvement on abnormal structural and functional consequence of heart characterized by increase in interventricular septum thickness, decrease in left ventricular stroke volume, and decrease of right ventricular tissue Doppler systolic velocity (Shivalkar et al., 2006).

Central sleep apnea (CSA) is a less common sleep disorder that cyclic loss of central ventilatory driving force is lost. Pusalavidyasagar et al.

(2007) discovered that although patients in both OSA and CSA groups have similar diagnostic AHI, AHI and central apnea during CPAP trial are significantly higher for patients with CSA than OSA (p<0.0001).

Additionally, patients with CSA have more CPAP interface problems including CPAP mask removal and air hunger or dyspnea. These findings indicate that CSA patients may need better alternative treatment to

eliminate the central apnea events (Pusalavidyasagar et al., 2007).

If patients who are not adaptable to CPAP for medical or psychological reasons, removable oral appliance fitted to the teeth during sleep is also recommended as an efficient way to improve breathing disturbance, hypertension, and quality of life (Bloch, 2006). Additionally, reduction of excess weight for obese patient, upper airway surgery, and treatment of nasal obstruction for patients due to chronic rhinitis, nasal polyposis, or nasal sepal deviation are also alternative choices (Bloch, 2006). Although various soft tissue surgery used for treatment of OSA have been proposed, which, however, remains controversial. However, adeno-tonsillectomy has been successful performed in patients with adeno-tonsillar hypertrophy for both adult (Bloch, 2006) and children (Guilleminault et al., 2005; Taman et al., 2006).

Treatment of moderate OSA patients using acupuncture was also investigated by Freire et al (2007). Their finding indicates that acupuncture is effectively in the improvement of AHI and treatment of OSA. Results obtained from PSG and questionnaires (SF-36 and ESS) both demonstrate the above findings.

Medication administration was also used to treat patients with mild to moderate OSA, although it is insufficient to improve patients with severe OSA compared to CPAP (Sangal et al., 2007). Biogenic amine reuptake inhibitors, including protriptyline (non-selective norepinephrine reuptake inhibitor) and fluoxetine (selective serotonin reuptake inhibitor), were reported to be able to improve sleepiness for patients with OSA. One investigation reported that it barely improve RDI (Hanzel et al., 1991) while others had no objective changes (Brownell et al., 1982; Smith et al., 1983). Recently, Sangal et al. (2007) administrated atomoxetine, a selective norepinephrine reuptake inhibitor, to 15 subjects who have been diagnosed with sleep disorders and finished the complete study. Similar

to previous investigations, the results showed that atomoxetine significantly decrease sleepiness, quantified by ESS and clinical global impression (CGI), but did not significantly decrease RDI.

Pediatric OSA is usually caused by adenotonsillar hypertrophy (Guilleminault et al., 2005; Brouillette et al., 2000), hence adenotonsillectomy is often considered as alternative treatment in addition to CPAP (Guilleminault et al., 2005).