The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in sleep

Abstract

Sleep unmasks a highly sensitive hypocapnia-induced apnoeic threshold, whereby apnoea is initiated by small transient reductions in arterial CO(2) pressure (P(aCO(2))) below eupnoea and respiratory rhythm is not restored until P(aCO(2)) has risen significantly above eupnoeic levels. We propose that the 'CO(2) reserve' (i.e. the difference in P(aCO(2)) between eupnoea and the apnoeic threshold (AT)), when combined with 'plant gain' (or the ventilatory increase required for a given reduction in P(aCO(2))) and 'controller gain' (ventilatory responsiveness to CO(2) above eupnoea) are the key determinants of breathing instability in sleep. The CO(2) reserve varies inversely with both plant gain and the slope of the ventilatory response to reduced CO(2) below eupnoea; it is highly labile in non-random eye movement (NREM) sleep. With many types of increases or decreases in background ventilatory drive and P(aCO(2)), the slope of the ventilatory response to reduced P(aCO(2)) below eupnoea remains unchanged from control. Thus, the CO(2) reserve varies inversely with plant gain, i.e. it is widened with hyperventilation and narrowed with hypoventilation, regardless of the stimulus and whether it acts primarily at the peripheral or central chemoreceptors. However, there are notable exceptions, such as hypoxia, heart failure, or increased pulmonary vascular pressures, which all increase the slope of the CO(2) response below eupnoea and narrow the CO(2) reserve despite an accompanying hyperventilation and reduced plant gain. Finally, we review growing evidence that chemoreceptor-induced instability in respiratory motor output during sleep contributes significantly to the major clinical problem of cyclical obstructive sleep apnoea.

Figure 1. Schematic representation of the factors influencing sleep-induced breathing instabilities

A, Cheyne-Stokes respiration in heart failure; B, periodic breathing clusters in hypoxia. C and D isolated ventilatory overshoots followed by hypopnea (C) or apnoea (D). The ventilatory overshoot is determined by: (a) increased magnitude of chemoreceptor stimuli, which in turn are dependent upon the duration of any preceding apnoea or hypopnoea, the functional residual capacity and the metabolic rate; (b) the gain of the chemoreceptor response, which in part depends upon state of consciousness; and (c) the translation of respiratory drive to ventilation which is dependent upon the prevailing upper airway resistance. Following the ventilatory overshoot a continued excitatory short-term potentiation (STP) of respiratory motor output favours stabilization of breathing pattern. The effectiveness of STP as a stabilizer will depend upon the magnitude and duration of the preceding stimulus. Inhibitory effects opposing STP (and causing apnoea) include: lung stretch at high V_T which will have a carry-over inhibitory effect, baroreceptor stimulation coincident with the rising systemic pressure during the overshoot phase which also contributes to a reduced respiratory motor output to both the pump and upper airway musculature, and transient hypocapnia. ‘Inertia’ refers to the continued short-term inhibition of inspiratory drive, prolongation of apnoea and delayed resumption of rhythmic respiration in the face of a P_aCO2 which increases to above eupnoeic levels.

Figure 2. The effects of changing background ventilatory drive on the gain of the ventilatory responsiveness to CO₂ below eupnoea, on ‘plant gain’ and on the CO₂ reserve (ΔP_ETCO2 eupnoea – apnoea) in sleeping dogs and humans

Data are plotted on separate isometabolic lines for dogs (CO₂ flow (V̇_CO2) = 150 ml min⁻¹) and for humans (V̇_CO2 = 250 ml min⁻¹). The diagonal dashed or continuous lines join eupnoeic and apnoeic points and their slopes indicate the gain below eupnoea of the ventilatory response to hypocapnia in each condition. The height of the vertical bar above the isometabolic line indicates the increase in V̇_A required to reduce the P_aCO2 to the apnoeic threshold (i.e. the inverse of plant gain). The CO₂ reserve is the difference in P_ACO2 between eupnoea and the apnoeic threshold. Note in the sleeping dog: (a) that the slope of the CO₂ response below eupnoea remained unchanged during hyper- or hypoventilation; (b) the required increase in V̇_A to reach apnoea under background conditions of hyperventilation via metabolic acidosis (Δ V̇_A = 1.4 1 min⁻¹) is about twice that required in control and almost five times that required with the background condition of hypoventilation via metabolic alkalosis (0.3 l min⁻¹); (c) the greater protection against apnoea during these backgrounds of hyper- versus hypoventilation are due solely to the change in G_p. Similarly, almitrine infusion (see bottom panel) caused hyperventilation, with no significant influence on the slope of the ventilatory response to CO₂ below eupnoea. However, in hypoxia (bottom panel) note the increased slope (versus control) of V̇_A—P_aCO2 relationship between eupnoea and the apnoeic threshold in dogs and especially in humans and in chronic heart failure (CHF) patients with Cheyne-Stokes periodic respiration (CSA). Thus in these latter two examples the CO₂ reserve is narrowed significantly despite the background hyperventilation and reduced plant gain. (Data compiled from Xie et al. 2001, ; Nakayama et al. 2003; and from author's laboratory.)

Figure 3. Apneic threshold lability

A, polygraph record in a tracheostomized dog during NREM sleep of a pressure support trial (PSV) during 5 h of metabolic acidosis achieved via oral acetazolamide administration (arterial pH = 7.34, [HCO₃⁻] 16 mequiv l⁻¹, P_aCO2 30 mmHg). The protocol used to determine the apnoeic threshold required several trials of incremental increases in PSV. Note that with metabolic acidosis a tracheal pressure (P_M) of over 20 cmH₂O, an increase in V_T of over 2× baseline eupnoea and a reduction in P_ETCO2 of 7 mmHg was required to cause apnoea and subsequent periodic breathing. B, polygraph record of a pressure support trial in NREM sleep during 1 h of metabolic alkalosis via i.v. NaHCO₃ (arterial pH = 7.51 [HCO₃⁻]= 35 mequiv l⁻¹, P_CO2= 44 mmHg). Note that a tracheal pressure of 9 cmH₂O induced via PSV was required to cause apnoea and subsequent periodic breathing. Contrast the CO₂ reserve of 3 mmHg (eupnoea – apnoeic threshold ΔP_CO2) in this condition of background hypoventilation with that of 7 mmHg in the condition of background hyperventilation via metabolic acidosis (Fig. 3A). C, polygraph record of a pressure support trial in NREM sleep after ∼1 h of hypoxia (P_aO2= 47 mmHg, P_aCO2= 31 mmHg). Despite a similar level of background hyperventilation as with metabolic acidosis (see Fig. 3A), in hypoxia the CO₂ reserve (eupnoeic P_ETCO2 – apnoeic threshold P_ETCO2) was reduced by one-half, because hypoxia increased the slope of the CO₂ response below eupnoea. (Also see Fig. 2, bottom panel.) Note, in the 3 PSV trials shown in Fig. 3A–C, that diaphragm EMG amplitude is reduced on the first breath of PSV, an effect which we also found when P_ETCO2 was held normocapnic throughout PSV trials. These non-chemoreceptor, neuro-mechanical inhibitory effects of PSV averaged reductions of 5–20% in EMG_di and 30% prolongations of TE (Nakayama et al. 2002).

Figure 4. The effects of one night of hypoxic exposure (F_IO2= 0.11) on periodic breathing and middle cerebral artery (MCA) blood flow during NREM sleep in the healthy human

Shown are signal averaged data over 150 periodic breathing cycles in a single healthy subject. These data are representative of those found in six additional subjects. Each periodic cycle averaged 22 s in duration and consisted of three hyperpnoeic tidal breaths followed by an 8–12 s apnoea. Note the average 30% increase in MCA blood velocity (CBF) as determined by Doppler ultra-sound measurements and the increase in mean arterial pressure (MAP) which began at the termination of the apnoea and peaked during the ventilatory overshoot phase. Immediately following the ventilatory overshoot, CBF fell 10% below baseline control (data from authors' laboratory). A transfer function analysis of the gain, phase and coherence between MCA flow velocity and MAP changes showed that changes in cerebral blood flow throughout the cycle always led those in MAP. Based on this correlative analysis and previous ganglionic blockade studies of breath-hold apnoea in awake subjects (Przybylowski et al. 2003), we attribute the increases in CBF to the transient hypoxaemia caused by the apnoeas and the subsequent decreases in CBF below baseline to the transient hypocapnia caused by the ventilatory overshoot. These marked increases in CBF may exacerbate brain extra-cellular fluid (ECF) hypocapnia, thereby reducing the CO₂ reserve and precipitating apnoea and periodic breathing. SaO₂, arterial O₂ saturation.