Respiratory long-term facilitation is a form of neuronal plasticity that is induced following exposure to intermittent hypoxia. Long-term facilitation is characterized by a progressive increase in respiratory motor output during normoxic periods that separate hypoxic episodes and by a sustained elevation in respiratory activity for up to 90 min after exposure to intermittent hypoxia. This phenomenon is associated with increases in phrenic, hypoglossal or carotid sinus nerve inspiratory-modulated discharge. The examination of long-term facilitation has been steadily ongoing for approximately 3 decades. During this period of time a variety of animal models (e.g. cats, rats and humans), experimental preparations and intermittent hypoxia protocols have been used to study long-term facilitation. This review is designed to summarize the strengths and weaknesses of the models, preparations and protocols that have been used to study LTF over the past 30 years. The review is divided into two primary sections. Initially, the models and protocols used to study LTF in animals other than humans will be discussed, followed by a section specifically focused on human studies. Each section will begin with a discussion of various factors that must be considered when selecting an experimental preparation and intermittent hypoxia protocol to examine LTF. Model and protocol design recommendations will follow, with the goal of presenting a prevailing model and protocol that will ultimately ensure standardized comparisons across studies.

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PurposeTo determine the impact of arousal state on the magnitude of the hypoxic ventilatory response (HVR − Δ VE/Δ SaO2) and ventilatory long‐term facilitation (vLTF).Methods5 healthy male subjects were exposed to IH on two occasions. The IH protocol consisted of 12‐2 minute episodes of hypoxia (PETO2 – 50 mmHg) in the presence of PETCO2 levels sustained 3 mmHg above baseline. Each episode was followed by a 2 minute normoxic recovery period with the exception of the last recovery period which was 30 minutes in duration. One IH trial was completed during wakefulness, with the other completed during sleep.ResultsThe HVR was greater during wakefulness compared to sleep in all participants (0.8 ± 0.2 vs. 0.5 ± 0.1 L/min/% SaO2, p = 0.06). Moreover, minute ventilation was greater during recovery compared to baseline, during both wakefulness and sleep (Wakefulness – 22.5 ± 1.8 vs. 18.6 ± 1.5 L/min, p = 0.03; Sleep – 15.2 ± 1.8 vs. 14.3 ± 1.8 L/min, p = 0.02). However, the magnitude of vLTF when standardized to baseline was significantly greater during wakefulness compared to sleep (1.21 ± 0.07 vs. 1.07 ± 0.02, p = 0.05).ConclusionsExposure to IH elicits vLTF during both wakefulness and sleep. However, the magnitude of the HVR and vLTF is significantly reduced during sleep compared to wakefulness.Funding: VA‐Merit Award