A Periodic breathing: novel experimental models to develop dynamic therapies

Abstract

<h3>Background</h3> Periodic breathing (PB) is a common complication of heart failure (HF), characterised by oscillations in CO₂ and ventilation and associated with increased morbidity and mortality. Studying potential interventions for PB is difficult, because it is highly variable. We propose two experimental models and test two new dynamic therapies that target CO₂ oscillations directly. <h3>Methods and Results</h3> First, we aimed to produce a human model of PB using pacemakers. Pacemakers were manipulated in twelve pacemaker recipients, six with HF (EF=23.7±7.3%) and six without, to induce oscillations experimentally. Second, we applied a real-time algorithm of pre-emptive dynamic exogenous CO₂ administration, and tested different timings. We found that cardiac output alternation by pacemaker successfully induced CO₂ and ventilatory oscillations. Dynamic CO₂ therapy, when delivered coincident with hyperventilation, attenuated 64% of the experimentally-induced oscillations in end-tidal CO₂: SD/mean 0.06±0.01 untreated vs 0.04±0.01 with treatment (p&lt;0.0001) and 0.02±0.01 in stable state. This translated to a 53% reduction in induced ventilatory oscillations: SD/mean 0.19±0.09 untreated vs 0.14±0.06 with treatment (p=0.001) and 0.10±0.03 in stable state. Notably end-tidal CO₂ did not significantly rise when dynamic CO2 was applied to the model (4.84±0.47 vs 4.91± 0.45 kPa, p=0.08). Furthermore, mean ventilation was also not significantly increased by dynamic CO₂ compared with untreated (0.13±0.02 vs 0.14±0.02 l/s, p=0.17). A second cohort of 14 patients with cardiac pacemakers (5 with HF (EF 27.6 ±13.9) and nine with normal systolic function) inhaled exogenous CO₂ that cycled from 0 to 4.25±1.8% every 30 s again inducing PB. In this group, cardiac output was then oscillated every 30 s in an attempt to alter the induced ventilatory oscillations. When cardiac output was oscillated from low too high every 30 s to coincide with peak ventilation, the degree of induced oscillation in et-CO₂ was reduced by 43% (SD/mean et-CO₂ during induced oscillations alone=0.08±0.02 vs SD/mean et-CO2 with alternation of cardiac output =0.05±0.02, p&lt;0.001). By reducing the degree of oscillation in et-CO₂, the degree of induced ventilatory oscillation was reduced 55% (SD/mean ventilation during induced oscillations alone=0.13±0.06 vs SD/mean ventilation with alternation of cardiac output=0.09±0.05, p&lt;0.01). <h3>Conclusion</h3> Both dynamic CO₂ administration and cardiac output modulation using a pacemaker, when correctly timed, successfully attenuated experimentally-induced ventilatory oscillations without increasing mean ventilation.