Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications

In patients with chronic heart failure (CHF), periodic breathing (PB) predicts poor prognosis. Clinical studies have identified numerous risk factors for PB (which also includes Cheyne-Stokes respiration). Computer simulations have shown that oscillations can arise from delayed negative feedback. However, no simple general theory quantitatively explains PB and its mechanisms of treatment using widely-understood clinical concepts. Therefore, we introduce a new approach to the quantitative analysis of the dynamic physiology governing cardiorespiratory stability in CHF.

An algebraic formula was derived (presented as a simple 2D plot), enabling prediction from easily acquired clinical data to determine whether respiration will be unstable. Clinical validation was performed in 20 patients with CHF (10 with PB and 10 without) and 10 healthy normal subjects. Measurements, including chemoreflex sensitivity (S) and delay (delta), alveolar volume (V(L)), and end-tidal CO(2) fraction (C), were applied to the stability formula. The breathing pattern was correctly predicted in 28 of the 30 subjects. The principal combined parameter (CS)x(delta/V(L)) was higher in patients with PB (14.2+/-3.0) than in those without PB (3.1+/-0.5; P:=0.0005) or in normal controls (2.4+/-0.5; P:=0.0003). This was because of differences in both chemoreflex sensitivity (1749+/-235 versus 620+/-103 and 526+/-104 L/min per atm CO(2); P:=0.0001 and P:<0.0001, respectively) and chemoreflex delay (0.53+/-0.06 vs 0.40+/-0.06 and 0.30+/-0.04 min; P:=NS and P:=0.02).

This analytical approach identifies the physiological abnormalities that are important in the genesis of PB and explicitly defines the region of predicted instability. The clinical data identify chemoreflex gain and delay time (rather than hyperventilation or hypocapnia) as causes of PB.