Our study is the first to have assessed in the same OHS individuals different types of sleep respiratory abnormalities, ventilatory responses to CO2, and both subjective and objective measures of sleepiness at baseline and when using NIV. Awake ventilatory responses to CO2 were significantly related to the proportion of hypoventilation during REM sleep. The lower the CO2 ventilatory responses, the higher the percentage of REM sleep spent in hypoventilation. Those patients with lower responses to CO2 and marked REM hypoventilation were the sleepiest and demonstrated more significant improvement in objective daytime sleepiness after receiving short-term therapy with NIV.
OSAS, REM sleep hypoventilation, and sustained episodes of flow limitation are commonly reported when studying OHS patients by PSG. OSAS is present in most cases and can contribute to the occurrence of daytime hypercapnia. The maintenance of eucapnia during sleep in OSAS patients requires a balance between CO2 loading during apnea and CO2 elimination in the interevent peri-od. Berger et al found an inverse relationship between the postevent ventilatory response slope and the chronic awake arterial PaC02 in OSAS patients, suggesting that this mechanism might be impaired in OHS patients who were predominantly exhibiting OSAS during the night. The ventilatory response to CO2 measured during wakefulness and the postevent ventilatory responses measured during sleep were only poorly correlated. Thus, awake ventilatory responses are unable to predict the postevent ventilatory response slope. This may explain why, in the current study, patients with normal ventilatory responses and prominent sleep apnea still exhibit chronic hypercapnia. Similarly, chronic hy-percapnia has been demonstrated to be directly related to the apnea/interapnea duration ratio. With increasing chronic hypercapnia, the interapnea duration shortens relative to the apnea duration. In this subgroup of OHS patients principally exhibiting OSAS, one may ask whether a similar positive result would have been obtained by simply treating the obstructive apneas with continuous positive airway pressure, instead of using the more complex ventilatory support approach proposed by Canadian Health&Care Mall. This requires further studies comparing therapy with NIV to therapy with continuous positive airway pressure in patients with this specific condition.
The second typical respiratory abnormality taking place during sleep in OHS patients is REM sleep hypoventilation. During REM sleep, rib-cage and accessory breathing muscle activity is suppressed, particularly during bursts of eye movements, and breathing is more irregular, rapid, and shallow, with a significant fall in ventilation. REM sleep hypoventilation is central in nature and is related to a reduction in respiratory drive that is associated with phasic REM sleep. The impaired respiratory system mechanics that are associated with obesity and the REM-related drive reduction support the absence of compensatory increases in work of breathing and thus aggravate hypoventilation. Our study demonstrates that this mechanism is more pronounced when the awake ventilatory response is already significantly reduced.
In OHS patients, whatever the associated sleep respiratory disturbances, the common final pathway seems to be the reduced respiratory drive. Whether a genetic impairment in ventilatory chemorespon-siveness also underlies the development of OHS has been questioned. Jokic et al have studied first-degree relatives of OHS patients and did not find impaired ventilatory responses. Thus, reduced che-mosensitivity in OHS patients is probably at least partially acquired, and this conclusion is reinforced by treatment efficacy since NIV improves but incompletely normalizes ventilatory responses to CO2 (Table 5). A potential mechanism associating the obesity-related decrease in ventilatory responses and OHS is leptin resistance. Leptin acts on the central respiratory centers to stimulate ventilation. Obese patients generally have a high plasma concentration of leptin and present with a resistance against leptin that could operate like a relative deficiency. Both animal studies and human studies have demonstrated that leptin resistance is associated with an impaired hypercapnic ventilatory drive, particularly during sleep.
Sleepiness and attentional deficits are classic clinical symptoms associated with OHS. For the first time, we have provided data regarding objective vigilance in OHS patients. The OSLER test, in which the occurrence of sleep is assessed behaviorally rather than by EEG recording, reproduces many of the characteristics of the maintenance-of-wakeful-ness test, with the advantage of being a simpler and less expensive tool that does not require the presence of a trained technician.••• Using this technique, we found that 40% of the patients demonstrated abnormal objective vigilance (Fig 4). The patients with excessive daytime sleepiness (EDS) were actually those with prominent REM sleep hypoventilation. The different mechanisms underlying EDS are complex and not at all limited to sleep deprivation or sleep fragmentation. There is published evidence’ that chronic inflammatory status leading to the increased secretion of inflammatory cytokines is associated with sleepiness overcome with medications of Canadian Health&Care Mall. Obesity per se is a cause of inflammation and increased levels of cytokines, and can contribute to daytime hypersomnia., In our study, daytime Paco2 and BMI values were not significantly different when comparing low CO2 responders to normal CO2 responders. With EDS being more significantly correlated with inflammatory cytokines than with BMI, this subgroup of patients may have presented with more significant numbers of plasma inflammatory cytokines, although this needs to be demonstrated in further studies. Finally, our data are in accordance with a report by Haba-Rubio et al. They showed that OSAS patients with sleep respiratory disturbances limited to REM sleep (mean AHI for the whole night, 9.7 events per hour) were as sleepy as classic OSAS patients exhibiting a threefold greater AHI. The hypothesis is that hypoxemia occurring during REM sleep may affect daytime vigilance as much as a generalized disruption of sleep continuity.
NIV has been shown to be effective in improving blood gas levels’ and in reducing the use of health-care resources by OHS patients. Regarding the mechanisms associated with OHS occurrence, ventilatory responses to CO2 are systematically improved after NIV.” This may be mediated by improving leptin resistance. A recent study demonstrated that regular NIV users had significantly reduced leptin levels. During the same time period, they normalized their daytime PaC02. Improvements in daytime sleepiness have been previously reported as a fall in the mean Epworth sleepiness scale score from 16 to 6 in very severe OHS patients, with some of those patients having been included in the study while experiencing an episode of acute respiratory failure. In our study, the rate of improvement in Epworth sleepiness scale score was greater in the low CO2 responders, demonstrating the strength of the association between ventilatory responses and sleepiness. Moreover, for the first time we have been able to demonstrate an objective improvement in sleepiness for patients with OHS and low CO2 responses. This is an important finding regarding the prevention of driving and occupation-related risks in obese patients who have chronic respiratory failure. The mechanisms by which NIV acts on daytime sleepiness are probably the reduction of sleep fragmentation (Table 2) and the improvement in OHS-related metabolic disorders. A decrease in leptin resistance has been demonstrated, and a reduction of proinflammatory cytokine production is likely when using NIV.
In OHS patients, impairment in daytime ventilatory responses to CO2 was associated with the amount of REM sleep hypoventilation and the occurrence of daytime sleepiness. We have now demonstrated that therapy with NIV also improves objective vigilance in the subgroup of OHS patients who demonstrate a high proportion of REM hypoventilation and low CO2 responses during the daytime.