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Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome

Open ArchivePublished:January 06, 2006DOI:https://doi.org/10.1016/j.rmed.2005.09.016

      Summary

      Flow limitation during sleep occurs when the rise in esophageal pressure is not accompanied by a flow increase which results in a non-rounded inspiratory flow shape. Short periods of flow limitation ending in an arousal or in a fall in SaO2 (hypopnea or upper airway resistance syndrome) are detrimental but the role of prolonged periods of flow limitation (PPFL) has not yet been clarified. This is important not only for diagnosis but also for nasal continuous positive airway pressure (CPAP) titration, especially for the automatic devices that need to be setup. The aim of this study was to analyze the effects of PPFL. We compared the behavior of the mean end-expiratory systemic blood pressure (SBP), end-tidal CO2, esophageal pressure and the pattern of breathing during a period of normal breathing at optimal (CPAP) and during PPFL at suboptimal CPAP in 14 patients with sleep apnea/hypopnea syndrome during a full polysomnography CPAP titration. The mean values of the parameters studied, at optimal and suboptimal CPAP were (1) SBP 92±13 vs. 91±15mmHg (P: ns). At suboptimal CPAP, swings of blood pressure were associated with changes in pleural pressure; (2) SaO2 97.5±1.2 vs. 96.5±1.6 (P: 0.03), (3) end-tidal CO2 43.5±4 vs. 49.5±4 (P:0.001); (4) oesophageal pressure, 10.5±4 vs. 37.6±15cmH2O (P:0.001) and (5) pattern of breathing: minute ventilation 6.6±1.4 vs. 6.1±1.2L/min (P: ns) and inspiratory time 1.24±0.3 vs. 1.66±0.4s (P:0.001). It can be concluded that PPFL induces significant physiological changes. Nevertheless, given the scant literature, clinical studies are warranted to elucidate the clinical role of these physiological changes.

      Keywords

      Introduction

      Sleep apnea and hypopnea syndrome (SAHS) is a common disorder that affects 2–4% of the adult population.
      • Duran J.
      • Esnaola S.
      • Rubio R.
      • Iztueta A.
      Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70yr.
      It is well known that in addition to apneas or hypopneas,
      • Gould G.A.
      • Whyte K.F.
      • Rhind G.B.
      • Airlie M.A.
      • Catterall J.R.
      • Shapiro C.M.
      • et al.
      The sleep hypopnea syndrome.
      other respiratory events such as the upper airway resistance syndrome (UARS)
      • Guilleminault C.
      • Stoohs R.
      • Clerk A.
      • Cetel M.
      • Maistros P.
      A case of excessive daytime sleepiness: the upper airway resistance syndrome.
      • Norman R.G.
      • Ahmend M.M.
      • Walsleben J.A.
      • Rapoport D.M.
      Detection of respiratory events during NPSG: nasal cannula/pressure sensor versus thermistor.
      • Montserrat J.M.
      • Ballester E.
      • Olivi H.
      • Reolid A.
      • Lloberas P.
      • Morelló A.
      • et al.
      Time-course of stepwise CPAP titration. Behaviour of respiratory and neurological variables.
      take place during sleep.
      Flow limitation occurs when increased esophageal pressure is not accompanied by a flow increase. Flow limitation depends on the interaction between the negative pleural pressure, which tends to collapse the upper airway, and upper airway muscle activity, which helps to keep the airway open. Flow limitation represents the physiological basis of the UARS also known as respiratory effort-related arousal (RERA). Its main characteristic is a flattening of the inspiratory flow shape which can be measured noninvasively by nasal prongs at diagnosis or by a pneumotachograph during continuous positive airway pressure (CPAP) titration.
      Although short periods of flow limitation (UARS or RERA) are accepted as disturbed breathing events.
      • Norman R.G.
      • Ahmend M.M.
      • Walsleben J.A.
      • Rapoport D.M.
      Detection of respiratory events during NPSG: nasal cannula/pressure sensor versus thermistor.
      The physiological and clinical role of prolonged periods of flow limitation (PPFL) has not been completely clarified.
      • Rees K.
      • Kingshott R.N.
      • Wraith P.K.
      • Douglas N.J.
      Frequency and significance of increased upper airway resistance during sleep.
      These events could play a role in the symptoms of some patients, for instance in those that show a lack of improvement when undergoing CPAP and in whom PPFL are not eliminated during titration. This could also exert an influence on the setup of the automatic CPAP devices.
      Although most CPAP titration clinical protocols recommend the elimination of apneas, hypopneas and snoring,
      • Rapoport D.M.
      Methods to stabilize the upper airway using positive pressure.
      there is no agreement on the need to correct PPFL. There are very few data that suggest that flow limitation should be eliminated during CPAP titration.
      • Meurice J.C.
      • Paquereau J.
      • Denjean A.
      • Patte F.
      • Series F.
      Influence of correction of flow limitation on continuous positive airway pressure efficiency in sleep apnoea/hypopnoea syndrome.
      However, the fact that PPFL can occur in healthy snoring subjects, e.g. in delta sleep, gives rise to some reservations concerning the need to correct PPFL during sleep. Given the inconclusive results of earlier studies, we made a reappraisal of the subject by analyzing, as a first step, the behavior of physiological parameters such as ventilation, blood pressure, pattern of breathing and end-tidal CO2. To this end, we induced PPFL by suboptimal CPAP during a full polysomnography (PSG) CPAP titration and compared to data with the results from periods of optimal CPAP.

      Materials and methods

      Fourteen male patients diagnosed with SAHS and requiring CPAP treatment
      • Barbe F.
      • Montserrat J.M.
      • Monasterio C.
      • Mayos M.
      • Diaz M.J.
      • Coloma R.
      Tratamiento del SAHS. Cuando y como tratar.
      were recruited. The mean data from these patients were: age: 52±8(sd) years; body mass index: 33±6kg/m2; apnea–hypopnea index: 59±8 events/h; CT90: 41±23; and Epworth sleepiness scale: 16±5. The Ethics Committee of the Hospital approved the protocol and all the patients gave their informed written consent.
      The measurements were made during a CPAP titration after training the patients in the use of nasal CPAP. Titration was performed during full PSG in the usual manner by measuring neurological and respiratory variables.
      • Montserrat J.M.
      • Ferrer M.
      • Hernandez L.
      • Farré R.
      • Viladagut G.
      • Navajas D.
      • et al.
      Effectiveness of CPAP treatment in daytime function in sleep apnea syndrome. A randomized controlled study.
      • Hernandez L.
      • Ballester E.
      • Farre R.
      • Badia J.R.
      • Lobelo R.
      • Navajas D.
      • et al.
      Performance of nasal prongs in sleep studies. Spectrum of flow-related events.
      • Rechtschaffen A.
      • Kales A.
      Manual of standardized terminology, technique and scoring system for sleep stages of human subjects.
      Apnea was defined as an absence of airflow of ⩾10s, and a hypopnea as any discernible airflow reduction for at least 10s, with a drop in oxygen saturation ⩾3% or final arousal.
      • Montserrat J.M.
      • Ferrer M.
      • Hernandez L.
      • Farré R.
      • Viladagut G.
      • Navajas D.
      • et al.
      Effectiveness of CPAP treatment in daytime function in sleep apnea syndrome. A randomized controlled study.
      • Hernandez L.
      • Ballester E.
      • Farre R.
      • Badia J.R.
      • Lobelo R.
      • Navajas D.
      • et al.
      Performance of nasal prongs in sleep studies. Spectrum of flow-related events.
      A pneumotachograph located between the leak valve and the mask allowed us to assess the different respiratory events and to compute minute ventilation, inspiratory time and breathing rate. Figure 1 shows different flow signal contours defining flow limitation. In addition, the following parameters were measured: (1) systemic blood pressure (SBP) by finger photoplethysmography (Finapress, Ohmeda, Englewood, CO), (2) end-tidal CO2 using TONOCAP 808289, Datex-Enstrom, Ins. Corp., Helsinki, sampled from the nose by a special device (878467-1, Datex-Engstrom, Helsinki, and (3) esophageal pressure.
      Figure thumbnail gr1
      Figure 1Examples of characteristic breathing patterns showing inspiratory flow limitation. All three inspiratory contours are flow limited, as indicated by the lack of roundness during inspiration. Flow limitation is due to upper airway collapse resulting from unbalance between high negative esophageal pressure and low upper airway muscle activity. In this figure inspiration corresponds to upwards flow.
      The study, carried out in sleep phase 2 or delta sleep, was initiated at CPAP=4cm H2O and nasal pressure was increased by 1cmH2O in response to repetitive events (apneas, hypopneas and flow limitation periods) until an optimal pressure was obtained. This was defined as the absence of repetitive events, a clearly rounded inspiratory flow shape and achievement of normal neurological sleep parameters. This optimal CPAP pressure was maintained for a prolonged period of time (20min) and then a gradual pressure reduction was applied to obtain PPFL lasting more than 10min (suboptimal CPAP). End-expiratory SBP, SaO2, end-tidal CO2, esophageal pressure and breathing pattern parameters were measured during the period of normal breathing and during PPFL. The variables measured during optimal and suboptimal CPAPs were compared using a paired t-test or Mann–Whitney test depending on normality. A level of P<0.05 was used for statistical significance.

      Results

      As the CPAP pressure level was increased over the course of the study, the apneas usually became hypopneas followed by PPFL and normal breathing. Figure 2 shows three different levels of CPAP in a representative patient. At 4cmH2O, apneas can be seen with large esophageal pressure swings and observable oscillations of blood pressure. At optimal CPAP, normal values of the different parameters were observed. The inspiratory flow shapes were rounded, with normal values of esophageal pressure. PPFL was found at suboptimal CPAP. The inspiratory flow shapes were clearly limited. The end-tidal CO2 increased, large esophageal pressure swings were observed and the SBP showed fluctuations.
      Figure thumbnail gr2
      Figure 2Three different levels of CPAP in a representative patient: (1) at the start (4cmH2O), apneas were present; (2) at optimal CPAP, breathing was normal and (3) at suboptimal CPAP, there was a period of flow limitation. In this step the end-tidal CO2 increased, large esophageal pressure swings were observed and the systemic blood pressure showed a fluctuation.
      Table 1 shows the main results. Mean end-expiratory SBP did not show a statistically significant change between optimal CPAP and suboptimal CPAP (PPFL). By contrast, SaO2 during PPFL decreased with respect to optimal CPAP, probably due to hypoventilation. End-tidal CO2 increased significantly during PPFL with respect to the values during optimal CPAP. As expected, the values of esophageal pressure swings were significantly higher during PPFL than during optimal CPAP. As regards, the breathing pattern, minute ventilation decreased approximately by 10% during PPFL compared with the minute ventilation during optimal CPAP, although not significantly. The decrease in minute ventilation was accompanied by a significant increase in the inspiratory time during the PPFL with respect to the inspiratory time during optimal CPAP.
      Table 1Mean end-expiratory systemic blood pressure, end-tidal CO2, SaO2, esophageal pressure, minute ventilation and inspiratory time during optimal CPAP and during the prolonged periods of flow limitation at sub-optimal CPAP.
      ParametersOptimal CPAP(Sub-Optimal CPAP)(p)
      Systemic blood pressure (mm Hg)92±1391±15n.s.
      SaO2 (%)97.5±1.296.5±1.60.03
      End-tidal CO2 (mm Hg)43.5±449.5±40.001
      Esophageal pressure (cmH2O)10.5±437.6±150.001
      Minute ventilation (l/s)6.6±1.46.1±1.2n.s
      Inspiratory time (s)1.24±0.31.66±0.40.001

      Discussion

      Our understanding of sleep apnea has evolved over time. Early research focused on pure obstructive sleep apnea i.e. total upper airway obstruction. This disorder corresponds to a static upper airway occlusion due to critical pressure being lower than atmospheric pressure. Subsequently, the concepts of hypopnea,
      • Gould G.A.
      • Whyte K.F.
      • Rhind G.B.
      • Airlie M.A.
      • Catterall J.R.
      • Shapiro C.M.
      • et al.
      The sleep hypopnea syndrome.
      UARS
      • Guilleminault C.
      • Stoohs R.
      • Clerk A.
      • Cetel M.
      • Maistros P.
      A case of excessive daytime sleepiness: the upper airway resistance syndrome.
      and short periods of flow limitation without a drop in SaO2 or arousal have been shown to play a role in SAHS.
      • Meurice J.C.
      • Paquereau J.
      • Denjean A.
      • Patte F.
      • Series F.
      Influence of correction of flow limitation on continuous positive airway pressure efficiency in sleep apnoea/hypopnoea syndrome.
      All these three events have the same pathophysiological basis: the upper airway closes partially during inspiration because of negative pleural pressure and low upper airway muscle activity. The result is a limitation of the inspiratory flow shape contour (Fig. 1). This phenomenon is also known as upper airway dynamic obstruction since the critical pressure is similar to atmospheric pressure.
      • Gold A.R.
      • Schwartz A.L.
      The pharyngeal critical pressure. The whys and hows of using nasal continuous positive airway pressure diagnostically.
      During CPAP titration, at suboptimal CPAP, PPFL occurs in association with negative swings of esophageal pressure.
      • Montserrat J.M.
      • Ballester E.
      • Olivi H.
      • Reolid A.
      • Lloberas P.
      • Morelló A.
      • et al.
      Time-course of stepwise CPAP titration. Behaviour of respiratory and neurological variables.
      Our study concerns the need to correct such PPFL. We have demonstrated that these periods have some adverse physiological consequences. Given the high pleural pressure swings occurring in these periods, it is conceivable that a hemodynamic workload is produced
      • Kaneko Y.
      • Floras J.S.
      • Usui K.
      • Plante J.
      • Tkacova R.
      • Kubo T.
      • et al.
      Cardiovascular effects of continuous positive airway pressure in patients with hearth failure and obstructive apnea.
      • Bradley T.D.
      • Hall M.J.
      • Ando S.
      • Floras J.S.
      Hemodynamic effects of simulated obstructive apneas in humans with and without heart failure.
      along with brief disruptions in cortical activity that could contribute to some clinical symptoms.
      • Chervin R.D.
      • Burns J.W.
      • Ruzicka D.L.
      Electroencephalographic changes during respiratory cycles predict sleepiness in sleep apnea.
      The description of the role of negative esophageal pressure swings in the genesis of systemic hypertension has also focused attention on cardiovascular consequences induced by PPFL.
      • Guilleminault C.
      • Sttohs R.
      • Shiomi T.
      • Kushida C.
      • Schnittger I.
      Upper airway resistance syndrome, nocturnal blood pressure monitoring, and borderline hypertension.
      • Ringler J.
      • Basner R.C.
      • Shannon R.
      • Manning H.
      • Weinberger S.E.
      • Schwartzstein R.
      • et al.
      Hypoxemia alone does not explain blood pressure elevations after obstructive apneas.
      • Edwards N.
      • Blyton D.M.
      • Kirjavainen T.
      • Kesby G.J.
      • Sullivan C.E.
      Nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in pre-eclampsia.
      • Stradling J.R.
      • Barbour C.
      • Glennon J.
      • Langford B.A.
      • Crosby J.H.
      Which aspects of breathing during sleep influence the overnight fall of blood pressure in a community population?.
      The role of the respiratory efforts has recently been shown to induce an immune response.
      • Vassilakopoulos T.
      • Roussos C.
      • Zakynthinos S.
      The immune response to resistive breathing.
      Finally, it has been demonstrated that correcting flow limitation and snoring in preeclamsia normalizes SBP.
      • Edwards N.
      • Blyton D.M.
      • Kirjavainen T.
      • Kesby G.J.
      • Sullivan C.E.
      Nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in pre-eclampsia.
      It therefore seems that PPFL could have some harmful effects.
      As far as clinical practice is concerned, there is little literature on this topic. The vigilance and cognitive test improvement in patients with corrected and uncorrected flow limitation were studied.
      • Meurice J.C.
      • Paquereau J.
      • Denjean A.
      • Patte F.
      • Series F.
      Influence of correction of flow limitation on continuous positive airway pressure efficiency in sleep apnoea/hypopnoea syndrome.
      This report showed that the correction of flow limitation together with the elimination of apnea, hypopnea and snoring with CPAP did not enhance sleep quality. The analysis of the changes in the maintenance of wakefulness time demonstrated a significantly greater scattering of final values when flow limitation was not corrected by nasal CPAP. This suggests an improvement in objective daytime performance. The authors concluded that flow limitation should be detected and corrected.
      In the light of our findings, and of other authors, it should be pointed out that the usual criterion for considering an optimal CPAP—suppression of apnea/hypopnea and snoring—may not be the most suitable approach. We suggest that high pleural pressure swings occurring in PPFL should be considered and normalized by achieving a rounded flow contour shape. This is important not just in diagnostic studies but also in the CPAP titration procedures whether manual or involving automatic devices where the settings need to be set-up. It goes without saying that further clinical studies are needed to provide more insight into the role of the physiological changes and clinical consequences induced by PPFL.

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