Possible mechanisms of arousal from respiratory stimuli include changes in PO(2), PCO(2), central respiratory drive, or respiratory mechanoreceptor activity. We sought to determine whether hypercapnia alone could induce arousal from sleep in four subjects with high (>/= C3) neurologically complete spinal cord injuries while on constant positive pressure mechanical ventilation (hence, respiratory mechanoreceptor activity remained constant). Subjects were chronically hypocapnic (mean baseline PET(CO(2)) = 21 mm Hg; range, 13-30 mm Hg). On the first night, the baseline rate of spontaneous awakenings was determined by polysomnography. On night two, FI(CO(2)) was increased rapidly in stable NREM sleep. Awakenings occurred in 19 of 19 trials within 5 min, with each subject waking and complaining of shortness of breath (mean time to arousal, 115 s; range, 26-264 s). It is unlikely that these were spontaneous, as the times to awakening during hypercapnia were much higher than during baseline conditions (p < 0.05). During rapidly induced hypercapnia, PET(CO(2)) overestimates the PCO(2) at the central chemoreceptors. To determine more precisely the PET(CO(2)) arousal threshold, PET(CO(2)) was increased slowly (approximately 2 mm Hg/min); arousal occurred at a mean PET(CO(2)) of 37 mm Hg (range, 23-45 mm Hg; mean change from baseline, 15.8 mm Hg, range, 10-20 mm Hg). Hence, both rapid and slow increases in PET(CO(2)) can induce arousal in humans in the absence of changes in respiratory mechanoreceptor activity.