In their study, Perger and colleagues1 report fluctuations in end-expiratory lung volume (EELV) in patients with Hunter-Cheyne-Stokes breathing (HCSB). Episodic alterations in tidal volume have long been recognized as the hallmark of HCSB, although fluctuations in EELV have been recognized only recently.2 Perger et al. report on a subset of 33 patients enrolled in the ADVENT-HF trial, and characterized 9 patients as having deflationary changes in EELV (“negative” pattern) and 24 patients as having inflationary changes in EELV (“positive” pattern).
The division of patients into the categories is predicated on what is judged to be resting lung volume (functional residual capacity, or FRC). While it is possible to reliably measure alterations in EELV with a respiratory inductive plethysmography, it requires fastidious attention to detail to avoid motion artifact or electrode drift.2 Achieving high-fidelity data is more challenging when a study is conducted at multiple sites.1 In the study by Perger et al.,1 quantitative volumetric measurements were not obtained and assignment to one of the groups was based on directional alterations in EELV. Perger et al.1 did not obtain robust data to demonstrate what constituted resting FRC in each individual patient, on which all subsequent calculations were predicated.
It was hypothesized the negative pattern was associated with worse heart failure and that the negative pattern should augment stroke volume by increasing intra-thoracic pressure. In the absence of any electromyography (EMG) measurements, the authors assume that the negative pattern developed because of activation of expiratory muscles (which are silent during normal passive expiration), thus driving lung volume below FRC, which is normally determined by elastic recoil of the respiratory system.
The key unanswered question is why patients with heart failure and a low ejection fraction should activate expiratory muscles to an extent that causes deflationary changes in EELV? The authors do not provide any explanation. We reason that patients with the most severe heart failure have a higher respiratory center drive, producing heightened activity of expiratory muscles and downward motion of EELV.
Activation of expiratory muscles consequent to elevated respiratory drive is not without precedence. This has been demonstrated in snorers and nonsnorers. Henke et al.3,4 measured inspiratory/abdominal expiratory muscle EMG using acutely implanted fine wire electrodes during sleep in snorers and nonsnorers. They also altered airway resistance using helium breathing. They found that expiratory muscles were recruited when airway resistance was high, and this occurred even when the increased resistance was confined to the inspiratory phase. That is, increased mechanical load was not immediately compensated for during sleep, and CO2 was retained. Respiratory drive increased, leading to the activation of expiratory muscles that could feasibly result in a lowering of EELV.
With regard to patients with heart failure, studies5,6 have shown that the subset of patients with HCSB and central sleep apnea have a more pronounced chemical drive to breathe than do patients with heart failure and without HCSB. Moreover, the magnitude of the chemosensitivity correlates with the severity of sleep-disordered breathing5 and heart failure.7 These experimental data are consistent with the findings of Perger et al.,1 in that patients with a negative HCSB pattern had higher NT-proBNP, worse NYHA functional class, and higher left ventricular wall tension.
While the changes in EELV may have resulted from increased respiratory drive leading to heightened activity of the expiratory muscles, augmented drive also produces an increase in inspiratory muscle activity, as shown by Brack et al.2 However, an increase in inspiratory muscle activity fosters inflationary changes in EELV.2 These changes occurred in 73% of patients (24/33) in the study by Perger et al. (the positive pattern).1 We also reason that augmented inspiratory drive leading to hyperventilation following central apneas will lower arterial CO2 pressure significantly; hypocapnia pre-disposes to the inhibition of the post-inspiratory inspiratory muscle activity, leaving expiratory muscle activity unopposed and, thus, facilitating reduction in EELV. Further systematic physiological studies using EMG of various groups of muscles and intrathoracic pressure are required to delineate the relative contribution of different muscle groups.
What are the pathophysiological consequences of activation of expiratory muscles during exhalation? If muscle groups are being recruited and driving EELV below resting FRC, the resulting increase in intrathoracic pressure constitute a double-edged sword. The work of breathing is increased by expiratory muscles; additionally, the elevated inspiratory drive fosters an increase in the work of breathing during inspiration, especially in patients with heart failure who have stiff congested lungs. Further, several hemodynamic and gas-exchange consequences also accrue. As lung volume drops below FRC, oxygen stores axiomatically decrease. With regards to hemodynamics, the consequences of increased intrathoracic pressure depend on both right and left ventricular function, and the status of preload and afterload.
Perger et al.1 correctly point out that increases in intrathoracic pressure, consequent to activation of expiratory muscles (responsible for lowering of lung volume below FRC), can have salutatory effects. By effecting a decrease in left ventricular transmural pressure, an elevated intrathoracic pressure augments stroke volume in some (but not all) patients with heart failure. But the benefits are not unalloyed. Beginning an inspiration from a low lung volume (below normal FRC) requires the generation of more negative intrathoracic-pressure swings consequent to the elastic recoil of the chest wall that is acting in an outward direction. Therefore, the left ventricular transmural pressure is increased which promotes a decrease in stroke volume.
Moreover, an elevation in intrathoracic pressure will impede venous return, and, if right ventricular stroke volume is preload dependent, an increase in intrathoracic pressure could decrease volume return to the left ventricle. Right ventricular stroke volume could be further impeded by increased pulmonary vascular resistance when lung volume decreases and the vascular bed is squeezed by increased intrathoracic pressure.8,9 Some of these mechanisms offer explanations as to why continuous positive airway pressure may be deleterious in some patients with heart failure,10 particularly in those whose central apnea is not suppressed by continuous positive airway pressure.10–13
The conduct of a multicenter trial, such as the ADVENT-HF trial,1 does not typically yield robust physiological measurements, and the status of central hemodynamics and activity of respiratory muscle groups among the included patients is not known. The findings, however, provide a stimulus for undertaking meticulous investigations of physiological mechanisms to better define different respiratory patterns in patients with HCSB.
NOTE ON TERMINOLOGY
In their study, Perger et al.1 use the term “Cheyne-Stokes respiration” or “CSR.” However, Hunter described this pattern of breathing almost 4 decades before Cheyne. For this reason, we refer to it in this commentary as “Hunter-Cheyne-Stokes breathing” or “HCSB.”13
The authors report no conflicts of interest.