Ventilatory long-term facilitation in humans.

Abstract

To the Editor: We read with interest the thoughtful editorial written by Iscoe and DiMarco about ventilatory facilitation in spinal cord injury in the January 1, 2014, issue of the Journal (1). The editorial highlighted the results from our recent study, which showed that ventilatory long-term facilitation can be induced in individuals with spinal cord injury (2). The editorial also highlighted some important issues, which will promote future investigations. These include determining the appropriate combination of intermittent hypoxia (i.e., the stimulus most often used to induce ventilatory long-term facilitation) and sustained hypercapnia, and exposure duration, to optimize long-term facilitation. In addition, Iscoe and DiMarco highlighted that intermittent hypoxia has the potential to enhance ventilatory function and improve quality of life. Although we agree with many of the points in the editorial, we are compelled to clarify some of the comments. The authors indicated that the record of long-term facilitation is suspect, which we believe is incorrect. Multiple studies from independent laboratories over the last 40 years have conclusively documented that intermittent hypoxia can lead to long-term facilitation in a multitude of species, including humans (3). The authors also suggested that long-term facilitation in our study lasted for a short time (i.e., 30 min) compared with the duration typically reported in anesthetized laboratory animals. However, the length of time long-term facilitation was sustained in our subjects is unknown, because ventilation was not recorded for longer than 30 minutes (2). A query regarding whether spinal cord injury is necessary to manifest the response was also raised. However, prior studies in humans without spinal cord injury have established that long-term facilitation can be induced under similar conditions. Indeed, we modeled our experimental paradigm based on this published literature (4–7). It is correct that ventilatory long-term facilitation could not be induced in neurologically intact humans initially, because carbon dioxide was not controlled at levels slightly above baseline values (8). However, the seminal paper of Harris and colleagues (5), which employed the appropriate control experiments, clearly showed that ventilatory and genioglossus muscle long-term facilitation were induced after exposure to intermittent hypoxia if carbon dioxide levels were rigorously controlled above baseline values. This finding has been replicated in a number of studies in both healthy individuals (5, 7, 9) and individuals with sleep apnea (4, 6, 7). Indeed, although the findings were not included in the present article, we established that ventilatory long-term facilitation was abolished during the end-recovery period in our subjects with spinal cord injury if carbon dioxide levels were not sustained. The role of carbon dioxide in the manifestation of long-term facilitation in humans also explains Iscoe and DiMarco’s quandary that long-term facilitation was induced in our study, but was absent in the study of Diep and colleagues (10), despite similar stimuli. The manner in which these stimuli were applied varied between investigations. In our present and previous investigations, carbon dioxide was sustained slightly above baseline values throughout the intermittent hypoxia protocol, during both the application of intermittent hypoxia and recovery periods, when ventilatory long-term facilitation typically manifests. In the study by Diep and colleagues (10), carbon dioxide was not maintained during periods of recovery. Consequently, hypocapnia was evident (see Figure 2 in Ref. 10) and ventilatory long-term facilitation was not, as was the case in previous investigations (5, 8). We believe that some of the answers to the mysteries of ventilatory long-term facilitation in humans have been answered, but many questions remain. The fundamental knowledge that has been established by our recent study—namely, that the long-term facilitation can be evoked after chronic spinal cord injury in humans—will allow for subsequent focus on the following questions. What is the combination of intermittent hypoxia and sustained carbon dioxide that evokes the greatest increase in breathing? What other rehabilitation modalities can be combined with intermittent hypoxia? Finally, what are the best outcome measures to determine the impact that ventilatory facilitation has on recovery of respiratory function after spinal cord injury in humans.