Respiratory events in heart failure

J Sleep Res. (2014) 23, 347–357

Sleep–wake fluctuations and respiratory events during Cheyne–Stokes respiration in patients with heart failure GIAN DOMENICO PINNA1, ELENA ROBBI2,3, FABIO PIZZA4,5, ANGELO C A P O R O T O N D I 3 , M A R I A T E R E S A L A R O V E R E 3 and R O B E R T O M A E S T R I 1 1 Department of Biomedical Engineering, Fondazione S. Maugeri – IRCCS, Montescano, Italy, 2Sleep Laboratory, Department of Pneumology, Fondazione S. Maugeri – IRCCS, Montescano, Italy, 3Department of Cardiology, Fondazione S. Maugeri – IRCCS, Montescano, Italy, 4 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy and 5Istituto delle Scienze Neurologiche di Bologna – IRCCS, AUSL di Bologna, Bologna, Italy

Keywords hybrid approach, respiratory-event diagram, state instability Correspondence Gian Domenico Pinna, Servizio di Bioingegneria, Fondazione S. Maugeri – IRCCS, Istituto Scientifico di Montescano, 27040 Montescano (PV), Italy. Tel.: +39-0385 247256; fax: +39-0385 61386; e-mail: [email protected] Accepted in revised form 12 October 2013; received 13 May 2013 DOI: 10.1111/jsr.12109

SUMMARY

Fluctuations in sleep–wake state are thought to contribute to the respiratory instability of Cheyne–Stokes respiration in patients with heart failure by promoting the rhythmic occurrence of central apnea and ventilatory overshoot. There are no data, however, on the relationship between vigilance state and respiratory events. In this study we used a novel method to detect the occurrence of state transitions (time resolution: 0.25 s, minimum duration of state changes: 2 s) and to assess their time relationship with apnoeic events. We also evaluated whether end-apnoeic arousals are associated with a ventilatory overshoot. A polysomnographic, daytime laboratory recording (25 min) was performed during Cheyne–Stokes respiration in 16 patients with heart failure. Automatic state classification included wakefulness and nonrapid eye movement sleep stages 1–2. As a rule, wakefulness occurred during hyperpnoeic phases, and non-rapid eye movement sleep occurred during apnoeic events. Ninety-two percent of the observed central apneas (N = 272) were associated with a concurrent wakefulness ? non-rapid eye movement sleep ? wakefulness transition. The delay between wakefulness ? non-rapid eye movement sleep transitions and apnea onset was 0.3 [ 3.1, 3.0] s [median (lower quartile, upper quartile); P = 0.99 testing the null hypothesis: median delay = 0], and the delay between non-rapid eye movement sleep ? wakefulness transitions and apnea termination was 0.2 [ 0.5, 1.2] s (P = 0.7). A positive/negative delay indicates that the state transition occurred before/ after the onset or termination of apnea. Non-rapid eye movement sleep ? wakefulness transitions synchronous with apnea termination were associated with a threefold increase in tidal volume and a twofold increase in ventilation (all P < 0.001), indicating ventilatory overshoot. These findings highlight that wakefulness ? non-rapid eye movement sleep ? wakefulness transitions parallel apnoeic events during Cheyne– Stokes respiration in patients with heart failure. The relationships between state changes and respiratory events are consistent with the notion that state fluctuations promote ventilatory instability.

INTRODUCTION A remarkably high proportion of patients with heart failure experience Cheyne–Stokes respiration (CSR) both during nighttime and daytime (Brack et al., 2007; La Rovere ª 2013 European Sleep Research Society

et al., 2007; Oldenburg et al., 2007; Yumino et al., CSR has been shown to be associated with a clinical status and prognosis (Bitter et al., 2011; et al., 2007; Javaheri et al., 2007a; La Rovere 2007).

2009). worse Brack et al.,

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The mechanisms responsible for CSR have not been completely elucidated (Javaheri and Dempsey, 2007b; Yumino and Bradley, 2008). Although it is largely accepted that an instability in the chemoreflex control of breathing is the main determinant of periodic oscillations in ventilation (Cherniack and Longobardo, 1986; Javaheri and Dempsey, 2007b), fluctuations in sleep–wake state (i.e. state instability) are thought to play an important role in promoting the rhythmic occurrence of central apnea and hyperventilation (Javaheri and Dempsey, 2007b; Yumino and Bradley, 2008). According to this view, the apnoeic threshold, i.e. the level of arterial carbon dioxide tension (PaCO2) below which ventilation ceases during non-rapid eye movement (NREM) sleep, is close to the eupnoeic PaCO2.in some patients with heart failure (Xie et al., 2002). Consequently, any transient increase in ventilation is likely to lower PaCO2 below the threshold and induce apnea. Because of the cessation of ventilation, PaCO2 increases, and when the chemical drive becomes strong enough to reach the arousal threshold, arousal occurs, thereby restoring the awake ventilatory response in a condition of arterial hypercapnia. This results in a ventilatory overshoot that, as sleep resumes, drives PaCO2 below the apnoeic threshold again, leading to a new cycle of apnea and hyperpnoea. Thus, this process would involve the cyclical transition from wakefulness to NREM sleep, predisposing to the occurrence of apnea, followed by the opposite transition from sleep to wakefulness, leading to ventilatory overshoot and hyperventilation. Although several investigations have reported a high number of arousals during CSR in patients with heart failure (Hanly et al., 1989; Naughton et al., 1993), surprisingly no study has addressed the relationship between sleep–wake fluctuations, central apneas and ventilatory overshoots. This lack of data is likely due to the fact that traditional scoring of polysomnographic recordings, being based on the analysis of fixed 30-s epochs, is not suitable to detect continuous fluctuations in state. Another important problem arises from the fact that sleep–wake transitions are often characterized by complex and variable electroencephalogram (EEG) patterns (Ogilvie, 2001; Santamaria and Chiappa, 1987), making visual identification of state changes difficult and very subjective. We hypothesized that if state instability is involved in the development of CSR and central apnea in patients with heart failure, apnoeic events would be associated with a concurrent transition from wakefulness to NREM sleep, and that this transition would be followed by an arousal. Furthermore, arousals would be accompanied by a ventilatory overshoot. The purpose of this study was to test this hypothesis using a novel methodology for continuous detection of fluctuations between wakefulness and NREM 1–2 sleep (Pinna et al., 2012). This approach allowed us to detect state transitions with a time resolution of 0.25 s, rather than every 30 s as in conventional polysomnography, and to consider state changes as short as 2 s. Moreover, it allowed us to identify the occurrence of wake–sleep–wake transitions objectively,

and to accurately assess their temporal relationship with apnoeic events. All studies were performed in a quiet laboratory in the morning. This laboratory setting allowed us to reliably measure a set of ventilatory parameters relevant to the objectives of the study. Previous studies from our and other groups have shown that CSR is very common in this condition (La Rovere et al., 2007; Ponikowski et al., 1999), and that it is clinically relevant (La Rovere et al., 2007; Ponikowski et al., 1999). Moreover, the condition is associated with an unstable EEG state (Maestri et al., 2010), which is similar to its manifestation during nighttime (Hanly et al., 1989). MATERIALS AND METHODS Subjects Subjects for the study were recruited from consecutive patients with chronic heart failure who were referred to our Heart Failure Unit for periodic follow-up evaluation. The diagnosis of heart failure was based on clinical signs and symptoms, and on the evidence of structural or functional cardiac abnormalities as defined by the guidelines of the European Society of Cardiology (McMurray et al., 2012). Eligible patients were >18 years old, with left ventricular ejection fraction (LVEF)

Sleep-wake fluctuations and respiratory events during Cheyne-Stokes respiration in patients with heart failure.

Fluctuations in sleep-wake state are thought to contribute to the respiratory instability of Cheyne-Stokes respiration in patients with heart failure ...
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