Ventilatory changes during intermittent hypoxia: importance of pattern and duration

Intermittent hypoxia is encountered in life more often than sustained hypoxia. The purpose of this article is to summarize the long-term effects of intermittent hypoxia on control of breathing. Emphasis is given to intermittent hypoxia associated with recurrent apneas and with brief repeated ascents to high altitude. Reported responses to chronic recurrent apneas include both depressed and enhanced hypoxic ventilatory responses (HVR). In addition, recurrent apneas are often associated with depression of the hypercapnic ventilatory response (HCVR). On the other hand, intermittent hypoxia associated with repeated ascents to high altitude augments HVR with little or no influence on the HCVR. In a rat model, prolonged exposure to intermittent hypoxia simulating recurrent apneas selectively enhances carotid body sensitivity to acute hypoxia and induces long-lasting activation of baseline activity, whereas intermittent hypoxia simulating repeated ascents to high altitude has little or no effect on peripheral chemoreceptor activity. Thus the mechanisms by which episodic hypoxia alter HVR appear to differ and seem to depend on the paradigm of intermittent hypoxia. Prolonged episodic hypoxia also leads to long-term facilitation (LTF) of respiratory motor output in humans and in experimental animals. Recent studies on experimental animals suggest the involvement of HIF-1 transcription factor in inducing enhanced HVR in response to chronic recurrent apnea pattern. Future studies are needed to identify the molecular and cellular signaling pathways associated with intermittent hypoxia and their impact on ventilatory control during hypoxia and hypercapnia.