Repetitive hypoxia followed by persistently increased ventilatory motor output is referred to as long-term facilitation (LTF). LTF is activated during sleep after repetitive hypoxia in snorers. We hypothesized that LTF is activated in obstructive sleep apnea (OSA) patients. Eleven subjects with OSA (apnea/hypopnea index = 43.6 +/- 18.7/h) were included. Every subject had a baseline polysomnographic study on the appropriate continuous positive airway pressure (CPAP). CPAP was retitrated to eliminate apnea/hypopnea but to maintain inspiratory flow limitation (sham night). Each subject was studied on 2 separate nights. These two studies are separated by 1 mo of optimal nasal CPAP treatment for a minimum of 4-6 h/night. The device was capable of covert pressure monitoring. During night 1 (N1), study subjects used nasal CPAP at suboptimal pressure to have significant air flow limitation (>60% breaths) without apneas/hypopneas. After stable sleep was reached, we induced brief isocapnic hypoxia [inspired O(2) fraction (FI(O(2))) = 8%] (3 min) followed by 5 min of room air. This sequence was repeated 10 times. Measurements were obtained during control, hypoxia, and at 5, 20, and 40 min of recovery for ventilation, timing (n = 11), and supraglottic pressure (n = 6). Upper airway resistance (Rua) was calculated at peak inspiratory flow. During the recovery period, there was no change in minute ventilation (99 +/- 8% of control), despite decreased Rua to 58 +/- 24% of control (P < 0.05). There was a reduction in the ratio of inspiratory time to total time for a breath (duty cycle) (0.5 to 0.45, P < 0.05) but no effect on inspiratory time. During night 2 (N2), the protocol of N1 was repeated. N2 revealed no changes compared with N1 during the recovery period. In conclusion, 1) reduced Rua in the recovery period indicates LTF of upper airway dilators; 2) lack of hyperpnea in the recovery period suggests that thoracic pump muscles do not demonstrate LTF; 3) we speculate that LTF may temporarily stabilize respiration in OSA patients after repeated apneas/hypopneas; and 4) nasal CPAP did not alter the ability of OSA patients to elicit LTF at the thoracic pump muscle.

Long-term facilitation (LTF) is a prolonged increase in ventilatory motor output after episodic peripheral chemoreceptor stimulation. We have previously shown that LTF is activated during sleep following repetitive hypoxia in snorers (Babcock MA and Badr MS. Sleep 21: 709-716, 1998). The purpose of this study was 1) to ascertain the relative contribution of inspiratory flow limitation to the development of LTF and 2) to determine the effect of eliminating inspiratory flow limitation by nasal CPAP on LTF. We studied 25 normal subjects during stable non-rapid eye movement sleep. We induced 10 episodes of brief repetitive isocapnic hypoxia (inspired O(2) fraction = 8%; 3 min) followed by 5 min of room air. Measurements were obtained during control and at 20 min of recovery (R(20)). During the episodic hypoxia study, inspiratory minute ventilation (Vi) increased from 6.7 +/- 1.9 l/min during the control period to 8.2 +/- 2.7 l/min at R(20) (122% of control; P < 0.05). Linear regression analysis confirmed that inspiratory flow limitation during control was the only independent determinant of the presence of LTF (P = 0.005). Six subjects were restudied by using nasal continuous positive airway pressure to ascertain the effect of eliminating inspiratory flow limitation on LTF. Vi during the recovery period was 97 +/- 10% (P > 0.05). In conclusion, 1) repetitive hypoxia in sleeping humans is followed by increased Vi in the recovery period, indicative of development of LTF; 2) inspiratory flow limitation is the only independent determinant of posthypoxic LTF in sleeping human; 3) elimination of inspiratory flow limitation abolished the ventilatory manifestations of LTF; and 4) we propose that increased Vi in the recovery period was a result of preferential recruitment of upper airway dilators by repetitive hypoxia.

Episodic hypoxia (EH) is followed by increased ventilatory motor output in the recovery period indicative of long-term facilitation (LTF). We hypothesized that episodic hypoxia evokes LTF of genioglossus (GG) muscle activity in humans during non-rapid eye movement sleep (NREM) sleep. We studied 12 normal non-flow limited humans during stable NREM sleep. We induced 10 brief (3 minute) episodes of isocapnic hypoxia followed by 5 minutes of room air. Measurements were obtained during control, hypoxia, and at 5, 10, 20, 30 and 40 minutes of recovery, respectively, for minute ventilation (V̇I), supraglottic pressure (P SG ), upper airway resistance (R UA ) and phasic GG electromyogram (EMG GG ). In addition, sham studies were conducted on room air. During hypoxia there was a significant increase in phasic EMG GG (202.7±24.1% of control, p<0.01) and in V̇I (123.0 ±3.3% of control, p<0.05); however, only phasic EMG GG demonstrated a significant persistent increase throughout recovery (198.9±30.9%, 203.6±29.9% and 205.4±26.4% of control, at 5, 10, and 20 minutes of recovery, respectively, p<0.01). In multivariate regression analysis, age and phasic EMG GG activity during hypoxia were significant predictors of EMG GG at recovery 20 minutes. No significant changes in any of the measured parameters were noted during sham studies. Conclusion: 1) EH elicits LTF of GG in normal non-flow limited humans during NREM sleep, without ventilatory or mechanical LTF. 2) GG activity during the recovery period correlates with the magnitude of GG activation during hypoxia, and inversely with age.

We wished to determine the severity of posthypoxic ventilatory decline in patients with sleep apnea relative to normal subjects during sleep. We studied 11 men with sleep apnea/hypopnea syndrome and 11 normal men during non-rapid eye movement sleep. We measured EEG, electrooculogram, arterial O(2) saturation, and end-tidal P(CO2). To maintain upper airway patency in patients with sleep apnea, nasal continuous positive pressure was applied at a level sufficient to eliminate apneas and hypopneas. We compared the prehypoxic control (C) with posthypoxic recovery breaths. Nadir minute ventilation in normal subjects was 6.3 +/- 0.5 l/min (83.8 +/- 5.7% of room air control) vs. 6.7 +/- 0.9 l/min, 69.1 +/- 8.5% of room air control in obstructive sleep apnea (OSA) patients; nadir minute ventilation (% of control) was lower in patients with OSA relative to normal subjects (P < 0.05). Nadir tidal volume was 0.55 +/- 0.05 liter (80.0 +/- 6.6% of room air control) in OSA patients vs. 0.42 +/- 0.03 liter, 86.5 +/- 5.2% of room air control in normal subjects. In addition, prolongation of expiratory time (Te) occurred in the recovery period. There was a significant difference in Te prolongation between normal subjects (2.61 +/- 0.3 s, 120 +/- 11.2% of C) and OSA patients (5.6 +/- 1.5 s, 292 +/- 127.6% of C) (P < 0.006). In conclusion, 1) posthypoxic ventilatory decline occurred after termination of hypocapnic hypoxia in normal subjects and patients with sleep apnea and manifested as decreased tidal volume and prolongation of Te; and 2) posthypoxic ventilatory prolongation of Te was more pronounced in patients with sleep apnea relative to normal subjects.