Elsevier

Sleep Medicine

Volume 11, Issue 6, June 2010, Pages 545-551
Sleep Medicine

Original Article
The effect of sildenafil on sleep respiratory parameters and heart rate variability in obstructive sleep apnea

https://doi.org/10.1016/j.sleep.2010.02.010Get rights and content

Abstract

Objective

To evaluate the magnitude of effects of sildenafil on respiratory parameters and heart rate variability (HRV) in slow wave sleep (SWS) and REM sleep of patients with severe obstructive sleep apnea (OSA).

Methods

Thirteen male patients with untreated severe OSA (aged 43 ± 10 years, body mass index of 26.7 ± 1.9 kg/m2) were studied on two nights, one with sildenafil 50 mg and one with a placebo, in a double-blind, randomized fashion. All-night polysomnography and HRV were simultaneously recorded. Short-term HRV measures were performed in apnea-free intervals. Respiratory parameters were separately assessed in non-REM and REM sleep and compared to total sleep time (TST). Short-term HRV analysis was conducted in samples with regular respiration obtained in SWS and REM sleep.

Results

Comparing to placebo, during sildenafil night there was an increase in apnea–hypopnea index (AHI) in TST and also in non-REM and REM sleep. Increase in central AHI occurred in non-REM sleep; increase in obstructive AHI and decrease in oxyhemoglobin saturation occurred in both non-REM and REM sleep. Additionally, an increase in arousal index and in low/high frequency component of HRV ratio (LF/HF) was significant only in REM sleep. Correlation between sleep architecture and respiratory parameters were more frequent in non-REM sleep for placebo and in REM sleep for sildenafil.

Conclusion

In severe OSA, the use of sildenafil 50 mg at bedtime plays a detrimental role on respiratory parameters in both non-REM and REM sleep, fragmentation in REM sleep, and a prolonged increase in LH/HF component of HRV after resumption of ventilation.

Introduction

A concern regarding the increasing percentage of men using selective phosphodiesterase-5 (PDE-5) inhibitor drugs to treat erectile dysfunction [1] is justified by the magnifying effect of sildenafil on the respiratory events in severe OSA, as previously demonstrated by our group [2]. In this previous study we speculated that nasal congestion, frequently reported by sildenafil users [3], may underlie the increase in number and duration of obstructive respiratory events. In addition, ventilation–perfusion mismatch may be attributed to the nitric oxide (NO)-dependent pulmonary vasodilatory effect of sildenafil, occurring in the absence of ventilation, with consequent enhancement in oxyhemoglobin desaturation. Besides a deleterious impact of NO-increased bioavailability on hemodynamic parameters in severe OSA, the decrease in percentage of SWS after sildenafil, in comparison to placebo, might evidence OSA severity, as has been proposed by other authors [4], [5], [6].

Clinically, OSA is very much a REM-sleep related disease [7], however, the degree of sleep synchronization also influences the magnitude of hypoxemia, intensity of upper airway occlusion, and arousability [8], [9]. The low synchronization of REM sleep contrasts with the highly synchronized slow wave sleep (SWS, defined as the sum of non-REM sleep stages 3 and 4) also in terms of impact on heart frequency. Taking into account the influence of sleep stage and respiration on HRV, this study was conducted with the aim to evaluate to which extent the NO-mediated effects of sildenafil act upon respiratory and HRV parameters in SWS and REM sleep. The primary endpoint was to separately assess central and obstructive respiratory events and the distribution of arousals in both non-REM and REM sleep. As a second outcome, HRV parameters were analyzed in apnea-free samples during SWS and REM sleep.

Section snippets

Methods

The present study is an extension of an earlier project and was conducted based on experimental data obtained from 13 patients prospectively enrolled in our previous double-blind, randomized, controlled study on the effect of sildenafil in sleep parameters in severe OSA [2].

Details of the study design, sampling plan, and methodology have been reported elsewhere [2]. In brief, 13 of 49 middle-aged men with OSA consecutively recruited for this study were selected (age 53.1 ± 9.8 years, BMI 26.7 ± 1.9 

Results

The 13 studied patients were evaluated during sleep after placebo or sildenafil 50 mg by means of polysomnography and HRV simultaneously recorded. Some of the results of the present study have been reported previously [2].

Comparison of apnea–hypopnea index per hour of TST, non-REM sleep time and REM sleep between placebo and sildenafil are illustrated in Fig. 1. The increase in AHI (central plus obstructive events) in TST after sildenafil, in comparison to placebo [mean ± SE (CIs), 48.1 ± 20.6

Discussion

The most important finding in this study is that in OSA patients, sildenafil increased apnea–hypopnea index not only as a whole, but also specifically in non-REM (central and obstructive events) and in REM sleep (obstructive events) compared to placebo. In addition to the previously described effect of sildenafil in decreasing SWS percentage and increasing desaturation index [2], the present results clarify that the lack in concomitant arousal enhancement may be attributed to the decreased

Conclusion

In conclusion, the present study not only confirms our findings that the use of sildenafil at bedtime plays a detrimental role in apnea events of severe OSA patients, but also demonstrates the extent of such effects on the cardiovascular system. Exacerbation of apnea in both non-REM and REM sleep, fragmentation in REM sleep, and a prolonged increase in LH/HF component of HRV after resumption of ventilation were observed in severe OSA patients after a single dose of sildenafil 50 mg at bedtime.

Acknowledgements

This study was supported by grants of CEPID-FAPESP, Sao Paulo, Brazil and Associação Fundo Incentivo a Psicofarmacologia. The authors would like to thank Mrs. Francisca Veloso for the support in all steps of this study.

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