Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO 2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain . 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited.Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance "strength") rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects.Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO 2 stimulation.Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain-consequent to increased chemosensitivity and delay-the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = 20.68) oscillations (P , 0.001 for all, both groups combined).Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population.Keywords: instability; loop gain; Cheyne-Stokes respiration; heart failure; chemosensitivity

For disease states characterized by oscillatory ventilation, an ideal dynamic therapy would apply a counteracting oscillation in ventilation. Modulating respiratory gas transport through the circulation might allow this. We explore the ability of repetitive alternations in heart rate, using a cardiac pacemaker, to elicit oscillations in respiratory variables and discuss the potential for therapeutic exploitation. By incorporating acute cardiac output manipulations into an integrated mathematical model, we observed that a rise in cardiac output should yield a gradual rise in end-tidal CO2 and, subsequently, ventilation. An alternating pattern of cardiac output might, therefore, create oscillations in CO2 and ventilation. We studied the effect of repeated alternations in heart rate of 30 beats/min with periodicity of 60 s, on cardiac output, respiratory gases, and ventilation in 22 subjects with implanted cardiac pacemakers and stable breathing patterns. End-tidal CO2 and ventilation developed consistent oscillations with a period of 60 s during the heart rate alternations, with mean peak-to-trough relative excursions of 8.4 ± 5.0% (P < 0.0001) and 24.4 ± 18.8% (P < 0.0001), respectively. Furthermore, we verified the mathematical prediction that the amplitude of these oscillations would depend on those in cardiac output (r = 0.59, P = 0.001). Repetitive alternations in heart rate can elicit reproducible oscillations in end-tidal CO2 and ventilation. The size of this effect depends on the magnitude of the cardiac output response. Harnessed and timed appropriately, this cardiorespiratory mechanism might be exploited to create an active dynamic responsive pacing algorithm to counteract spontaneous respiratory oscillations, such as those causing apneic breathing disorders.

We examine the potential to treat unstable ventilatory control (seen in periodic breathing, Cheyne-Stokes respiration, and central sleep apnea) with carefully controlled dynamic administration of supplementary CO2, aiming to reduce ventilatory oscillations with minimum increment in mean CO2. We used a standard mathematical model to explore the consequences of phasic CO2 administration, with different timing and dosing algorithms. We found an optimal time window within the ventilation cycle (covering ∼1/6 of the cycle) during which CO2 delivery reduces ventilatory fluctuations by >95%. Outside that time, therapy is dramatically less effective: indeed, for more than two-thirds of the cycle, therapy increases ventilatory fluctuations >30%. Efficiency of stabilizing ventilation improved when the algorithm gave a graded increase in CO2 dose (by controlling its duration or concentration) for more severe periodic breathing. Combining gradations of duration and concentration further increased efficiency of therapy by 22%. The (undesirable) increment in mean end-tidal CO2 caused was 300 times smaller with dynamic therapy than with static therapy, to achieve the same degree of ventilatory stabilization (0.0005 vs. 0.1710 kPa). The increase in average ventilation was also much smaller with dynamic than static therapy (0.005 vs. 2.015 l/min). We conclude that, if administered dynamically, dramatically smaller quantities of CO2 could be used to reduce periodic breathing, with minimal adverse effects. Algorithms adjusting both duration and concentration in real time would achieve this most efficiently. If developed clinically as a therapy for periodic breathing, this would minimize excess acidosis, hyperventilation, and sympathetic overactivation, compared with static treatment.

Dynamic CO(2) administration, delivered at an appropriate time during PB, can almost eliminate oscillations in et-CO(2) and ventilation. This dynamic approach might be developed to treat central sleep apnea, as well as minimizing undesirable increases in et-CO(2) and ventilation.