A common and effective treatment for OSA is nasal continuous positive airway pressure (CPAP). When air is pumped at positive pressure through a facemask, the patient's airway is kept open, reducing the number of apneas (respiratory suspensions) and hypopneas (reductions in airflow and oxygenation during sleep) With CPAP, the majority of patients are able to get their first good night's sleep in years.
We have conducted several therapeutic treatment studies using CPAP to see if the positive effects on sleep are also accompanied by a reversal of the many negative physiological effects of OSA, including elevated NE levels and adrenergic receptor desensitization.
Patients were assessed prior to and following either 1 or 2 weeks of treatment. CPAP treatment begins with a manual overnight CPAP titration of increasing steps of 1 to 2 cm H2O until unequivocal obstructive apneas or hypopneas are controlled.
We typically compare CPAP treatment to what we call placebo-CPAP (CPAP at an ineffective positive pressure to control apneic events). We have also compared CPAP to oxygen supplementation.
Nocturnal supplemental oxygen has been suggested by some as an alternative therapy in the nonsomnolent or the CPAP noncompliant OSA patient (Phillips, Schmitt, Berry, Lamb, Amin, and Cook 1990; Landsberg, Friedman, and AscherLandsberg 2001).
Equipment for the three treatment arms was similar and consisted of a CPAP generator (Aria LX CPAP System, Respironics Inc., Murrysville, PA), CPAP mask (Profile Light, Respironics Inc., Murrysville, PA) and tubing, heated humidifier (Fisher and Pykel HC199, Aukland, New Zealand) and oxygen concentrator (Alliance, Healthdyne Technologies Model 505, Marietta, GA). The concentrator can be switched to produce room air. The supplemental gas (room air or oxygen) is introduced into the CPAP system at the level of the humidifier.
In order to maintain the blind to treatment, subjects randomized to therapeutic CPAP receive active CPAP plus an oxygen concentrator that provides room air. Subjects randomized to placebo-CPAP receive subtherapeutic CPAP (<1 cm H2O at the mask) plus an oxygen concentrator providing room air. The placebo-CPAP treatment consists of a CPAP mask with 10 one-fourth inch drill holes for adequate room air exchange with pressure set at a constant 3 cm H2O. A pressure reducer is placed in the tubing between the CPAP unit and the modified mask.
With this system, the pressure at the mask is 0.5 cm H2O at end-expiration and 0 cm H2O during inspiration and the patients feel a gentle breeze at the nose. Those assigned to nocturnal oxygen receive placebo-CPAP plus an oxygen concentrator delivering oxygen at 3 l/min (FiO2 of 32 to 34% at the mask). Subjects are first tested on our Clinical Research Center, then sent home with their equipment until returning to the research center for their repeat testing.
15.5.1. CPAP Effects on NE levels and Adrenergic Receptors
We have found that CPAP treatment is effective in normalizing sympathetic nervous system activity in OSA, including the elevated levels of NE and NE excretion, and restoration of desensitized ß-adrenergic receptors (Ziegler, Mills, Loredo, Ancoli-Israel, and Dimsdale 2001).
We conducted a randomized, placebo-controlled trial of CPAP on sympathetic nervous activity in 38 patients with OSA (Ziegler et al. 2001). All of the patients had OSA. In this study, patients were randomized blindly to either CPAP or placebo CPAP treatment for 10 days. As shown in Fig. 15.5, CPAP, but not placebo CPAP, lowered daytime plasma NE levels by 23% (Ziegler et al. 2001).
Figure 15.5. The effect of CPAP and placebo CPAP treatment on plasma NE levels and daytime urinary NE levels. CPAP decreased NE levels (p < 0.04), differing from the effect of placebo treatment Urine NE excretion fell in the CPAP group (p < 0.001), differing from the effect of placebo (Ziegler et al. 2001).
CPAP also led to a lowering of daytime urine NE excretion levels by 36% (Fig. 15.5). The effect of CPAP treatment on nighttime urine NE levels did not differ from placebo treatment (data not shown).
CPAP treatment also helped normalize the sensitivity of lymphocyte ß2-adrenergic receptors. Recall earlier we showed that ß2-adrenergic receptors were desensitized in OSA. We found that CPAP increased ß-receptor sensitivity from 4.8 to 5.2 while ß-receptor sensitivity was slightly decreased in the placebo CPAP group (from 5.1 to 4.9) (p < 0.01).
Given the findings that CPAP reduces elevated NE levels and NE excretion, we wondered whether CPAP has these effects by altering the release and/or the clearance rate of NE (Mills, Kennedy, Loredo, Dimsdale, and Ziegler 2006). Considering prior observations that patients with OSA have a tendency toward diminished NE clearance and that CPAP reduces NE levels, we suspected that CPAP treatment would lead to an increase in NE clearance or perhaps a decrease in NE release rate. We randomized OSA patients to a 2-week therapeutic trial of CPAP, placebo CPAP or oxygen supplementation.
NE excretion and blood pressure were also assessed in these subjects. We evaluated the adequacy of urine collection by measures of volume and creatinine excretion. Urinary NE excretion was expressed in micrograms excreted per hour during wake (16 h, 06:00 to 22:00 h) and sleep (8 h, 22:00 to 06:00 h).
We concluded from these studies that CPAP is an effective treatment to restore more normal levels of sympathetic activity in OSA.
Prior to CPAP treatment, we found that the AHI was related to NE release rate (r = 0.385; p < 0.01) and day (r = 0.381; p < 0.01) and night (r = 0.313; p < 0.05) NE excretion rates. SaO2 < 90% (percent time less than 90% SaO2) correlated with NE release rate (r = 0.463; p < 0.01), plasma NE levels (r = 0.319, p < 0.05) and day (r = 0.583 p < 0.01) and night (r = 0.667; p < 0.01) NE excretion rates.
AHI was significantly reduced by CPAP (F = 28.9, p < 0.001) but not by oxygen or placebo CPAP treatment. SaO2 < 90% was significantly reduced by CPAP and oxygen (ps < 0.05) but not by placebo CPAP. Systolic (p < 0.013) and diastolic (p < 0.026) blood pressures were decreased in response to CPAP but not the oxygen or placebo CPAP.
Regarding the effects of CPAP on NE kinetics, 2 weeks of CPAP led to a significant increase in NE clearance (p < 0.01) (Fig. 15.6). NE clearance, volume of distribution, and half-life were unchanged following either oxygen or placebo CPAP.
As previously reported plasma NE levels were reduced following CPAP (p < 0.018) but unchanged following either oxygen or placebo CPAP. Daytime NE excretion was reduced following 2 weeks of CPAP treatment (p < 0.001) and oxygen treatment (p < 0.01) but unchanged following placebo CPAP.
Nighttime NE excretion was reduced following CPAP treatment only (p < 0.05). NE release rate was unchanged with any treatment (data not shown) (Mills et al. 2006).
In addition to examining the direct effects of treatment on NE kinetics, in an effort to better understand the role of NE in blood pressure responses to treatment, we conducted a series of multiple regression analyses examining possible predictors of posttreatment levels of systolic and diastolic blood pressure. Dependent variables were entered into the regression in blocks as follows—block 1: age, BMI, gender, and diagnosis of hypertension; block 2: pretreatment AHI, SaO2 < 90%, and the respective pretreatment blood pressure; block 3: pretreatment NE clearance, NE release rate, supine plasma NE, and daytime and nighttime NE excretion; block 4: posttreatment AHI, SaO2 < 90%; block 5: posttreatment NE clearance, NE release rate, supine plasma NE, and daytime and nighttime NE excretion.
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