Canadian HealthCare Mall: Discussion of Medroxyprogesterone Acetate in Obstructive Sleep Apnea
That medroxyprogesterone might be beneficial in patients with obstructive sleep apnea is suggested by the fact that such patients have abnormalities in respiratory regulation while awake. They may have marked reduction in respiratory drive during sleep. Reduction in the genioglossus EMG during sleep, indicating decreased respiratory drive to the upperairway muscles, is seen at the onset of and during episodes of apnea in patients with obstructive sleep apnea. It has been reasoned that a ventilatory stimulant might increase the output of the respiratory center to the muscles of the upper airway during sleep. Such increased stimulation could improve muscle tone and prevent collapse of the upper airway during sleep.
M edroxyprogesterone acetate has been found to be a moderate, sustained ventilatory stimulant in normal man. This effect, which is seen both at rest and during exercise, can be detected as early as 24 hours after administration. The respiratory stimulant effect of medroxyprogesterone has been employed in some cases of chronic mountain polycythemia, chronic obstructive pulmonary disease, and the obesity-hypoventilation sydrome.
In this study, analysis of the polysomnographic data shows the lack of effect of medroxyprogsterone in obstructive sleep apnea. There was no change in either the frequency or duration of apneic or disordered breathing episodes. Arterial desaturation during sleep was not ameliorated by medroxyprogesterone during either apneic or disordered breathing episodes.
To evaluate the effectiveness of a therapy for obstructive sleep apnea, it is necessary to examine multiple variables that are indicators of respiration during sleep. Use of any single variable may be misleading. For instance, patients 1 and 8 of our study appeared during treatment to show marked reduction in the number of apneic episodes per hour of sleep and in the time of apnea expressed as a percentage of total sleep time; however, both of these patients showed greater arterial oxygen desaturation during treatment. Patient 8 showed an increase in disordered breathing episodes during treatment as well. Patient 3 was the only one who showed marked reduction in the apnea index, the time of apnea as a percentage of total sleep time, and desaturation during apnea. Patient 3 was also the only patient in the entire group to have a substantial weight loss (13 kg [29 lb]) during treatment. No other patient lost more than 5 kg (11 lb) over the entire period of study. To descover the world of medical science is rather simple together with Canadian HealthCare Mall diigo website.
The measured changes in apnea and disordered breathing during and following treatment with medroxyprogesterone varied widely among patients. In view of the slightly decreased FEV1/FVC% found in some of the patients (Table 1), a possible cause of this variability might be subclinical upper-airway obstruction. Although no data were obtained on upper-airway morphometry, the lack of correlaton between the data on pulmonary function and the changes in apnea and disordered breathing suggests that differences in the degree of airway obstruction were not a major cause for the variability in the data. Another possible explanation for the variability in the response of patients might be that the same dose of medroxyprogesterone was given to all patients. The dose employed was similar to that administered for respiratory stimulation in patients with sleep apnea and other respiratory disturbances. While no adjustment was made for body weight, there was no significant correlation (Pearson product-moment test) between the dosage of medroxyprogesterone per kilogram of dosage body weight and measures of changes in breathing abnormalities such as the apnea index, apnea time, disordered breathing index, and disordered breathing time. Thus, it is unlikely that differences in dosage per weight were responsible for the variability in response. We conclude that the lack of statistical difference in parameters of breathing during sleep with or without medroxyprogesterone indicates that the changes observed in these parameters with the drug were probably random and not related to the drug. Random variation is also a plausible explanation for our finding of no difference between the drives measured during and after the discontinuation of therapy.
Our protocol did not include any studies with a placebo. Fortunately, lack of a placebo group is less important with the finding that medroxyprogesterone did not improve respiratory variables during sleep. Respiratory drive was measured in all patients to demonstrate that the expected increase in drive occurred and to document patients compliance. Administration of medroxyprogesterone in similar doses has been found to cause moderate sustained stimulation to ventilation in normal humans. The response was noted as early as 24 hours, with the maximal effect occurring at seven days.
The exact site where medroxyprogesterone exerts its ventilatory stimulant action is unclear. Cross-circulation studies in dogs suggest that peripheral chemo-receptors are not necessary for this response. Other conceivable peripheral mechanisms for improved ventilatory drive include alteration of pulmonary parenchyma or responses to vagally mediated stimuli. Medroxyprogesterone-related metabolites are capable of crossing the blood-brain barrier and could thus affect some central mechanism causing ventilatory stimulation. The ventilatory stimulant effect of medroxyprogesterone in these patients is shown by the increased mean slope for regression of minute ventilation of end-tidal Pco2. The findings of our study demonstrate that augmented ventilatory drive during wakefulness is not necessarily associated with improvement of the breathing disturbances during sleep.
The values for oxygen desaturation reported for each patient in Tkbles 2 and 3 are the mean of the lowest values found during each episode. As noted previously, during treatment, some patients had fewer episodes of apnea but a worsening of Sa02. Since increased respiratory drive and the consequent increase in respiratory effort during obstructed breathing may be associated with decreased saturation, it is possible that the greater desaturation may have been due to the effect of medroxyprogesterone on respiratory drive. Other possible explanations might include changes in sleeping posture or ventilation-perfusion relationships.
Two previous studies on the effect of medroxyprogesterone in patients with obstructive sleep apnea have shown varying results. Orr et al studied seven obese patients with obstructive sleep apnea prior to and after two to four weeks of administration of medroxyprogesterone acetate in doses similar to those used in our study. These investigators found no significant differences in the frequency or duration of apneas occurring before and during treatment. They noticed an improvement in cardiac failure in some of their patients, which they suggested might be related tq the anti-aldosterone diuretic effect of medroxyprogesterone. Three of their seven patients were hyper-capnic while awake. Of their four nonhypercapnic patients, two improved with medroxyprogesterone, and two did not. Orr et al did not present respiratory control data for their patients.
In the more recent study by Strohl et al, nine adult patients with obstructive sleep apnea were treated with 60 to 120 mg of medroxyprogesterone acetate per day. A subgroup of four of these patients responded to the drug. All four of the subgroup were obese, hyper-somnolent, and hypercapnic. Respiratory control data are unavailable for their patients. The subgroup described by Strohl et al probably represents a population similar to the obesity-hypoventilation syndrome that was studied earlier by Sutton et al. Medroxyprogesterone may be beneficial in the obese, hypersom-nolent hypercapnic patient. The patients included in our study had varying degrees of obesity but were nonhypercapnic. While hypercapnia and right heart failure may be seen late in the course of obstructive sleep apnea, the vast majority of patients when seen initially are nonhypercapnic. Our study indicates that in this large group of patients with obstructive sleep apnea who are nonhypercapnic during wakefulness, medroxyprogesterone stimulates ventilation but does not improve the breathing disturbances during sleep.