Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure

Abstract

Spontaneous day-time periodic breathing (sPB) constitutes a common phenomenon in systolic heart failure (HF). However, it is unclear whether PB during wakefulness could be easily induced and what are the physiological and clinical correlates of patients with HF in whom PB induction is possible. Fifty male HF patients (age 60.8 ± 9.8 years, left ventricle ejection fraction 28.0 ± 7.4%) were prospectively screened and 46 enrolled. After exclusion of patients with sPB the remaining underwent trial of PB induction using mild hypoxia (stepwise addition of nitrogen gas to breathing mixture) which resulted in identification of inducible (iPB) in 51%. All patients underwent assessment of hypoxic ventilatory response (HVR) using transient hypoxia and of hypercapnic ventilatory response (HCVR) employing Read's rebreathing method. The induction trial did not result in any adverse events and minimal SpO₂ during nitrogen administration was ∼85%. The iPB group (vs. non-inducible PB group, nPB) was characterized by greater HVR (0.90 ± 0.47 vs. 0.50 ± 0.26 L/min/%; p <0.05) but comparable HCVR (0.88 ± 0.54 vs. 0.67 ± 0.68 L/min/mmHg; p = NS) and by worse clinical and neurohormonal profile. Mean SpO₂ which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO₂ preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO₂ during induced PB (r = -0.49, p = 0.04). In summary, PB induction is feasible and safe in HF population using simple and standardized protocol employing incremental, mild hypoxia. Pathophysiology of iPB differs from sPB, as it relies mostly on overactive peripheral chemoreceptors. At the same time enhanced HVR might play a protective role against profound hypoxia during iPB.

Keywords: carotid body; induction; periodic breathing; peripheral chemoreceptors; peripheral chemoreflex.

FIGURE 1

Study protocol. A graphical depiction of the timeline and details of the periodic breathing (PB) induction, hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR) assessment.

FIGURE 2

Example of non-inducible periodic breathing (nPB). Continuous recording of oxygen saturation (SpO₂), tidal volume (TV), minute ventilation (MV), and end-tidal CO₂ (ETCO₂) during induction protocol. Nitrogen titration phase is depicted with solid arrow and final nitrogen flow-rate phase with blank arrow.

FIGURE 3

Example of inducible periodic breathing (iPB). Continuous recording of oxygen saturation (SpO₂), tidal volume (TV), minute ventilation (MV), and end-tidal CO₂ (ETCO₂) during induction protocol. Nitrogen titration phase is depicted with solid arrow and final nitrogen flow-rate phase with blank arrow.

FIGURE 4

Example of spontaneous periodic breathing (sPB). Continuous recording of oxygen saturation (SpO₂), tidal volume (TV), minute ventilation (MV), and end-tidal CO₂ (ETCO₂) during baseline phase recording.

FIGURE 5

Study flowchart. Graphical presentation of the distribution of patients enrolled into the study.

FIGURE 6

An example of the assessment of hypercapnic ventilatory response (HCVR) using rebreathing method. The slope of the regression line relating minute ventilation (MV) to end-tidal CO₂ (ETCO₂) constitutes a measure of HCVR (L/min/mmHg). Each solid point represents a single breath.

FIGURE 7

Differences in hypoxic ventilatory response (HVR, left panel) and hypercapnic ventilatory response (HCVR, right panel) between patients with non-inducible (nPB), inducible (iPB) and spontaneous periodic breathing (sPB). Data are presented as SD ± SEM. *p <0.05 for iPB vs. nPB, †p < 0.05 for sPB vs. nPB.

FIGURE 8

A schematic representation of the potential mechanism of PB induction. An increase in minute ventilation (MV) related to hypoxaemia leads to decrease in end-tidal CO₂ (ETCO₂) which results in hypoventilation (open arrow) precipitating the ongoing oscillations in ETCO₂ and MV (solid arrow indicates a rise in ETCO₂ following hypoventilation).