A number of uncontrolled trials have demonstrated the utility of CPAP in controlling SDB [105], reversing awake respiratory failure [93, 106], and improving quality of life [107] in patients with OHS. Improved ventilatory responses to hypercapnia with nocturnal CPAP have also been shown [62, 74]. To a large extent it is not surprising that a significant number of patients with OHS would respond to CPAP given the high incidence of upper airway obstruction in this population [11, 29, 66] and the relationship between severe OSA and hypercapnia [21, 37, 94]. By preventing apneas and hypopneas, acute accumulation of carbon dioxide would be prevented, helping to normalize not only oxygen saturation but also carbon dioxide. In addition, even low pressure CPAP (7 cmH₂O) has been shown to reduce inspiratory pressure swings and neural drive substantially in obese persons [45]. This is possibly due to offsetting the PEEPi that develops in the supine position in these individuals [45]. The volume-inflating effect of CPAP may also help to stabilize the upper airway via caudal traction on the trachea rendering it less collapsible [59], and improve oxygenation by increasing functional residual capacity.

Data from observational and controlled trials suggest that in up to 80 % of patients presenting with stable OHS to sleep laboratories, upper airway obstruction and nocturnal gas exchange are likely to be corrected by CPAP either during the first night of pressure titration [108] or following a period of bilevel therapy [93]. Similarly, in those patients presenting with acute respiratory failure requiring assisted ventilation initially, a significant proportion can be managed adequately with CPAP in the longer term [33, 92].

Several factors appear to distinguish those individuals responding to CPAP and those that “fail” CPAP (non-responders). In a study of “super” obese patients with OHS (BMI > 50 kg m⁻²), 43 % of subjects failed CPAP (defined in this study as > 20 % of TST spent with SpO₂ < 90 %) during the initial night of therapy [105]. Baseline awake blood gases and spirometric measurements could not distinguish CPAP responders from non-responders. However, CPAP non-responders were significantly more obese (BMI mean (SE): 62(2) versus 57(1) kg m⁻², p = 0.02) and spent more time with SpO₂ < 90 % while asleep during the diagnostic study night compared to those responding to CPAP [105]. In a study looking at patients with OHS initially managed with bilevel PAP therapy, Perez de Llano et al. [92] found that a higher FVC% predicted, less time spent with SpO₂ < 90 % and a higher AHI at baseline were characteristics of those able to be switched to longer term CPAP therapy. Taken together, these data suggest that in individuals with OHS in whom upper airway obstruction is the predominant mechanism underlying the development of hypercapnia , CPAP is likely to be effective long-term therapy. In contrast, where mechanical and neurohormonal factors arising from severe obesity are primarily driving the development of hypoventilation , an incomplete response to CPAP therapy is more likely [108]. At present, there are insufficient data regarding threshold values for AHI, BMI, or vital capacity (VC) which can predict an individual’s clinical response to CPAP, and overnight manual titration of PAP therapy remains the standard method of determining pressure needs. This is best carried out in a sleep laboratory, monitoring not only oxygen saturation but also some surrogate of carbon dioxide such as transcutaneous carbon dioxide monitoring to identify the degree to which sleep hypoventilation is corrected.

A major limitation in the evidence regarding the long term use of CPAP is the paucity of data regarding clinical outcomes. Most studies have followed patients managed with CPAP up to 3–6 months with regard to blood gases and quality of life [93, 107]. However, little is known about how these individuals fare compared to those managed with bilevel PAP therapy with regard to longer term adherence to therapy, treatment failure, improvement in cardiometabolic risk factors, or survival. It is also unclear what degree of residual breathing abnormality and hypoxemia can be accepted during the initial CPAP titration night without affecting longer term outcomes, since a progressive improvement in response to CPAP seems to be possible in some [93, 104, 105, 109].

Most of the literature regarding the management of OHS has focused on the use and outcomes of bilevel PAP therapy rather than CPAP. In many countries, OHS is now the main indication for home NPPV [14, 16]. Bilevel PAP therapy is generally introduced when sustained nocturnal hypoxemia persists despite correction of upper airway obstruction [65, 108], or if the patient is intolerant of CPAP [110]. However, the most effective mode of bilevel PAP therapy for OHS has yet to be determined, and there are very few studies comparing clinical outcomes with different modes of bilevel PAP in the longer term.

Until recently, no randomized trials had compared NPPV to conservative management in terms of its impact on sleep and breathing. Borel and colleagues [111] allocated 37 patients with OHS and mild chronic hypercapnia to either bilevel PAP or lifestyle counseling over a 1-month period. They demonstrated that bilevel PAP (ST mode) was significantly more effective in improving sleep and daytime blood gas parameters than counseling. Although both sleep macro- and microstructure improved significantly under bilevel PAP therapy, subjective daytime sleepiness did not improve to any greater extent than with the conservative management approach.

In a 3-month randomized study comparing CPAP to spontaneous mode fixed bilevel PAP, Piper et al. [93] found no difference between modes with respect to changes in awake PaCO₂, adherence to therapy, vigilance, or generic quality of life measures in 36 patients with OHS of mild to moderate severity. However, findings of this study are limited, as patients in whom sustained falls in oxygen saturation below 80 % for more than 10 min during an initial CPAP trial were not enrolled. Nevertheless, those randomized to CPAP therapy still spent 39 % of total sleep time with an oxygen saturation < 90 % at optimal pressures during their first night of CPAP therapy. However, after 3 months of treatment, CPAP was effective in normalizing nocturnal gas exchange in 30 of the 36 subjects. In a retrospective study of OHS patients with concomitant OSA, Mokhlesi et al. [108] reported no difference in the degree to which either of these two modes of PAP improved awake blood gases, suggesting that bilevel PAP therapy is not inherently superior to CPAP in patients with concomitant OSA so long as the PAP therapy used effectively controls SDB.

The majority of trials evaluating NPPV in OHS have compared ST mode bilevel PAP therapy with or without the addition of volume-targeted pressure support [112–115]. Although volume-targeted pressure support may increase ventilation and reduce carbon dioxide during sleep to a greater extent than standard fixed bilevel pressure support [112, 113, 115], clinically important differences between the two modes have yet to be shown. In a comprehensive study of 50 OHS patients (mean BMI 50 ± 7 kg m⁻²; PaCO₂ 49 ± 6 mmHg) randomized to volume-targeted pressure support or fixed pressure bilevel ST support over a 3-month period, no difference between modes was seen in terms of arterial blood gas improvement, weight loss, daytime sleepiness, quality of life or physical activity levels [114].

For patients who present in acute hypercapnic respiratory failure , or those without significant upper airway obstruction during sleep, bilevel support is generally used [33, 109, 116, 117]. Even in these groups, a switch to CPAP therapy may be possible longer term [92], with one study finding a significant proportion of patients presenting initially with purely sleep hypoventilation went on to develop OSA when taken off NPPV once hypercapnia was corrected [109].

A common approach for determining CPAP in patients with OHS and OSA is to perform an in-laboratory overnight titration study, increasing pressure to prevent obstructive apneic and hypopneic events [65, 75, 118]. If prolonged periods of flow limitation with persisting hypoxemia occur [65], pressure is further increased until the inspiratory flow pattern on the flow trace is normalized [105, 119], and SpO₂ is maintained > 90 % [65, 120]. Since persisting hypoventilation is most likely to occur during REM sleep, particular attention needs to be paid to gas exchange and breathing during this sleep stage. If supplemental oxygen has been added to maintain SpO₂ > 90 % in the absence of apneas and hypopneas, persisting hypoventilation may be masked. In these circumstances, transcutaneous carbon dioxide monitoring can be a useful tool in identifying the problem [121, 122] and guiding the choice of alternative interventions.

At present there is no evidence to support the safety or efficacy of using auto-titrating CPAP technology for either determining a fixed pressure to correct SDB or as a long-term therapy option in patients with OHS [123]. The algorithms used by auto-titrating CPAP devices have not been adequately evaluated in terms of the persistence of hypopneas that are not pressure responsive (i.e., hypopneas arising from reduced effort and hence decreased tidal volume rather than flow limitation and upper airway instability). In the unattended setting, oximetry is infrequently used during auto-titration studies. Consequently, ongoing hypoventilation and hypoxemia despite control of obstructive events may go unrecognized [124].

Despite the widespread use of NPPV for OHS [14, 16], there is limited evidence to guide what mode and settings most effectively manage this disorder, although general recommendations for the overnight titration of fixed bilevel PAP therapy have been published [120]. While the goals of NPPV are to prevent upper airway obstruction and reverse hypoventilation, therapy itself may induce abnormal breathing events, producing asynchrony between the patient efforts and support from the ventilator [125]. Inadequate or excessive settings may also induce various problems. Patients may not be aware of these events [126] nor may their presence be obvious during routine daytime clinical review [127]. However, asynchrony may contribute to patient discomfort, poor tolerance of therapy, or an incomplete response to treatment. Poor patient–machine synchrony occurs commonly and the importance of overnight monitoring to identify such problems and to improve the efficacy of nocturnal bilevel PAP is increasingly recognized. Consequently, PSG studies for bilevel titration is highly recommended to optimize settings and compare various modes of PAP therapy between different sleep stages and body positions [112, 120]. A systematic description of the types of respiratory events that may occur during NPPV has been developed with the aim of optimizing ventilatory support during PSG studies [128]. However, the relevance of these events with regard to adherence to therapy, quality of life, and survival has yet to be fully evaluated.

The spontaneous mode has been recommended as the default setting for bilevel PAP unless the patient is unable to trigger the machine consistently, or has a significant number of central events or a low spontaneous breathing rate [120]. Studies reporting positive outcomes with bilevel PAP in OHS patients have used both spontaneous and ST modes [15, 93, 114]. In order to determine if one mode offers greater benefits over another, Contal and colleagues [126] performed a randomized trial evaluating three different backup respiratory rate (BURR) settings over three consecutive nights in ten patients with OHS previously established on bilevel PAP. The three settings were spontaneous mode (i.e., no BURR), a low BURR (ST mode set at two breaths below the average nocturnal respiratory rate recorded over the previous 2 weeks, approx 11 breaths/min), and a high BURR (ST mode set at the nocturnal 95th percentile of respiratory rate of the past 2 weeks, approx 21 breaths/min). Compared to both ST mode settings, the AHI and the oxygen desaturation index were significantly higher in the spontaneous mode, with the majority of events being central or mixed in nature. There was little objective difference in sleep architecture or microarousal index between the three modes apart from a longer sleep latency in the spontaneous mode. Subjectively, patients noticed little difference in sleep quality and comfort between the spontaneous and ST modes. Based on these findings, the authors questioned the wisdom of using a spontaneous mode in this population. However, the protocol used in this study may have influenced the findings. The levels of IPAP and EPAP used across all three nights were not altered from the usual home settings which had previously been determined using only oximetry and transcutaneous carbon dioxide monitoring. The high rate of obstructive events persisting during the spontaneous and low BURR nights suggests the level of EPAP was insufficient to stabilize the upper airway. Repeated arousals from sleep due to upper airway obstruction could have contributed to breathing instability and central events [129]. Mean tidal volume and its variability were also higher during the spontaneous mode compared to the other modes. Although not statistically different, the mean overnight transcutaneous carbon dioxide was 3 mmHg lower during the spontaneous mode night, and this small reduction in carbon dioxide could have favored the development of central events. It is of interest however that in a post hoc analysis, Murphy and colleagues [114] found that patients who had a lower triggering rate (i.e., more machine controlled breaths) during NPPV experienced greater improvements in nocturnal and awake gas exchange and health-related quality of life (HRQoL). These findings provide some supporting evidence that using a mode with a BURR sufficient to achieve a more controlled mode of ventilation may be more effective in this population, and should be further evaluated [130].

Comprehensive guidelines for setting IPAP and EPAP levels and adjusting pressure support during in-laboratory titrations have been published [120]. While the general recommendation is to aim for tidal volumes based on 6–8 ml/kg ideal weight, values of 8–10 ml/kg may be more effective in OHS [12, 114]. Although it has been suggested that IPAP above 20 cmH₂O may be poorly tolerated [92], other studies have used pressures higher than this without affecting adherence [12, 114]. The EPAP level required to maintain upper airway patency can vary considerably between individuals, with some studies using a fixed pressure of 4–5 cmH₂O for all patients [12, 117, 131] while others have used up to 14–16 cmH₂O [29, 65, 114]. Appropriate nocturnal monitoring to adjust settings adequately, particularly EPAP, is important to ensure normalization of breathing pattern and gas exchange during sleep. However, significant residual upper airway obstruction or oxygen desaturation persists for many patients despite bilevel PAP therapy [114, 125, 132] (Fig. 4.3a and b). In many of the reported studies, NPPV settings have been determined by nocturnal oximetry and awake blood gases [15, 92, 131]. However, it may not be easy to judge the level of EPAP required to stabilize the upper airway in all sleep stages and body positions based on these two parameters alone. Importantly, sleep fragmentation and impaired sleep quality can occur in the absence of changes in SpO₂ or nocturnal carbon dioxide [125], but could nevertheless affect clinical outcomes or acceptance of therapy. These findings support the use of nocturnal polygraphy or PSG to titrate IPAP, EPAP, and BURR settings as well as adjusting other features of the bilevel device to optimize patient–ventilator interactions [125].

Baseline awake hypoxemia and the requirement for supplemental oxygen have both been found to be independent predictors of mortality in long-term retrospective studies in OHS populations [12, 29]. This has largely been attributed to the presence of pulmonary arterial hypertension (PAH), a common sequela of chronic hypoxemia [12]. Therefore, when NPPV alone is inadequate to maintain daytime and/or nocturnal SpO₂ greater than 90 %, supplemental oxygen is prescribed. Current recommendations and practices surrounding the prescription and titration of supplemental oxygen in OHS are based on studies in patients with COPD, despite the obvious pathophysiological differences between the two disorders.

Oxygen alone does not correct hypoventilation and may worsen symptoms and clinical complaints [133]. However, it appears to be prescribed for a significant number of patients with OHS as first line therapy [33]. As seen in other groups with hypoventilation, excessively high concentrations of supplemental oxygen producing hyperoxia are potentially harmful to individuals with OHS, and can lead to significant worsening of carbon dioxide levels and respiratory acidosis in some even during wakefulness [134, 135]. Importantly, more hypoxemic patients are more likely to experience larger rises in carbon dioxide with high concentrations of supplemental oxygen [134]. Based on the potential risks surrounding high concentration oxygen in people with OHS, oxygen flow rates should be carefully titrated to maintain SpO₂ within a target range (e.g., 88–92 %) [120, 135], whether during NPPV titration, for daytime use or in the acute care setting.

Supplemental oxygen is required in approximately 15–40 % of patients with stable OHS during NPPV initiation [29, 93, 108] and as many as 80 % of those commenced on domiciliary NPPV during an admission to hospital with acute respiratory failure [92]. After the initial phase of 1–3 months, an improvement in nocturnal and daytime gas exchange can be expected [104, 108]. At this time, the need for supplemental oxygen should be reassessed and can often be withdrawn, with only a small proportion (less than 10 %) of individuals with OHS requiring oxygen on a long-term basis [93, 108, 136].

Prior to adding nocturnal supplemental oxygen, NPPV settings should be optimally titrated to otherwise correct SDB and hypoventilation [120]. Residual hypoxemia despite NPPV may arise from the therapy itself related to large leaks or intolerance of high IPAP. Atelectasis or underlying parenchymal lung disease may also contribute to the problem [29]. Clinical guidelines recommend that oxygen be added into the NPPV circuit (via a T-connector at the device outlet) when awake supine SpO₂ is less than 88 % while breathing room air in the supine position, or after NPPV settings have been optimally titrated but SpO₂ remains less than 90 % for more than 5 min [120]. Oxygen flow rate should be commenced at 1 L/m and increased in 1 L/min increments every 5 min until a stable SpO₂ greater than 90 % is achieved [120]. Although these recommendations are not specific to patients with OHS, similar oxygen titration protocols have been successfully implemented in this group [12, 29, 46, 93, 108].