Obesity hypoventilation syndrome (OHS) has traditionally been defined as daytime hypercapnia (PaCO2 ≥ 45 mmHg) in obese individuals (body mass index [BMI] > 30 kg/m2) in the absence of another cause of hypoventilation. The risk of OHS increases as BMI increases and with the obesity pandemic there has been ongoing interest in timely diagnosis and initiation of effective therapies, especially given the significant morbidity and mortality that has been associated with OHS. This interest is reflected in the studies by Sivam and colleagues and Bouloukaki and colleagues published in this issue of the Journal of Clinical Sleep Medicine.1,2
Sivam and colleagues investigate the prevalence of isolated nocturnal hypercapnia in obese patients referred to an outpatient sleep unit for suspected sleep-disordered breathing.1 This study relies on a premise that OHS represents a clinical spectrum, whereby patients with isolated nocturnal hypoventilation may go on to develop daytime hypoventilation. In 2015, Manuel et al. proposed that obese individuals with an isolated increase in arterial base excess (BE) despite awake eucapnia represented OHS at the earliest stage.3 They compared ventilatory responses to hypoxia and hypercapnia in 71 obese subjects with either normal awake arterial blood gas measurements, awake hypercapnia or an isolated increase in BE with normal daytime PaCO2.3 The group with the isolated increase in BE had ventilatory responses to daytime acute hypoxic and hypercapnic challenge in between the normal and hypercapnic group. It was suggested that this group represented early OHS, implying OHS exists as a clinical spectrum. This group however, was not followed longitudinally and it remains unknown whether individuals with an isolated increase in BE will progress to develop daytime hypercapnia.
This concept of an OHS spectrum is adopted by Sivam and colleagues who study the prevalence of 5 stages of hypoventilation (0–IV), based loosely on a European Respiratory Society (ERS) Task Force on definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep.4 In contrast to the ERS classification, Sivam and colleagues use an awake arterialized earlobe capillary blood gas and polysomnography with transcutaneous CO2 monitoring to divide a cohort of 94 obese patients (BMI > 40 kg/m2) and without evidence of obstructive airways disease on spirometry into obstructive sleep apnea (OSA) without daytime or nocturnal hypercapnia (stage 0), nocturnal only hypercapnia with bicarbonate level < or ≥ 27 mmol/L (stages I–II) and daytime hypercapnia without and with comorbidities (stages III–IV). Using these definitions, they report a prevalence of 60.6% for OSA without daytime or nocturnal hypercapnia, 19.1% for nocturnal only hypercapnia and 17% for daytime hypercapnia. This OHS prevalence of 17% is in line with prior OHS prevalence estimates of 10% to 20% among obese patients with OSA referred to a sleep disorder center, but the mean BMI in this study population was 52.4 kg/m2. A higher OHS prevalence has previously been reported in patients with a BMI > 50 kg/m2.5–7 This study did not include those with a BMI < 40 kg/m2 and given the association between OHS and BMI, if a clinical spectrum of OHS does exist, then this may be a population of relevance for evaluating nocturnal hypercapnia. Similarly the authors do not provide data separating those with a bicarbonate level < or ≥ 27 mmol/L. This may also be of interest given recent opinion to expand the definition of OHS to include a standard bicarbonate > 27 mmol/L or arterial BE > 3 mmol/L due to the potential influences on PaCO2.8
The authors go on to try and identify predictors of nocturnal only hypercapnia. Emphasis is placed on supine measures and the supine awake oxygen saturation by finger pulse oximetry ≤ 93% and a supine awake arterialized capillary blood gas CO2 (PcCO2) of ≥ 45 mmHg were identified as the best predictors of nocturnal hypercapnia. A predictive model combining both variables improved sensitivity and while the authors propose consideration of these variables in the outpatient practice for early detection and treatment of isolated nocturnal hypercapnia, again it remains unknown whether this subset of obese patients with isolated nocturnal hypercapnia will go on to develop daytime hypercapnia if left untreated. An increase in PcCO2 was not observed with supine positioning in the OHS group. This was attributed to the possibility of a more decompensated ventilatory response in the OHS group compared to the isolated nocturnal hypercapnia group, such that positional change has less influence on awake gas exchange. Yet, it also remains possible, as mentioned by the authors, that isolated sleep hypoventilation represents a distinct OHS phenotype rather than a less advanced stage within an OHS severity. Similarly, it remains unclear whether the approximate 10% of patients with OHS, but without OSA, represents a distinct phenotype. It is not known whether obese patients with isolated nocturnal hypercapnia have the same associated morbidity and mortality described in patients with OHS (ie, daytime hypoventilation). Little information regarding medical comorbidities is provided for this particular cohort. It is also unknown whether interventions to improve nocturnal hypercapnia in obese individuals with isolated nocturnal hypercapnia will alter natural disease history or clinical outcomes. While this study provides new and important insights into the prevalence of isolated nocturnal hypercapnia in severely obese individuals, the clinical significance of isolated nocturnal hypercapnia remains to be determined.
Fortunately, effective therapies for OHS are available. Bouloukaki and colleagues2 add to existing, largely long-term observational data supporting positive airway pressure (PAP) effectiveness in improving gas exchange, sleepiness, quality of life, depressive symptoms and all-cause mortality.9,10 In a single center prospective study, Bouloukaki and colleagues followed 252 clinically stable patients who were newly diagnosed with OHS and OSA for a minimum of 2 years after initiation of PAP with either continuous PAP (CPAP) (37.7%) or bilevel PAP in spontaneous mode without a backup rate (62.6%). Median follow-up was 30 months. PAP therapy significantly improved gas exchange, the Epworth Sleepiness Scale, quality of life and depressive symptoms. In this observational cohort, mortality was low (11 patients or 5% died, mainly from cardiovascular disease). This lower than previously described mortality may be related to the fact that most patients had overall milder OHS (PaCO2 ≤ 50 mmHg) with fewer comorbidities, were clinically stable, and PAP adherence was high with a mean daily use of 6.0 ± 1.7 h/night.10–16 Patients in this study were followed very closely with individual counseling at 1 month, every 3 months for the first year, and every 6 months thereafter; this degree of close attention to adherence may not always be possible outside the research realm.
The magnitude of improvement in PaCO2 was associated only with PAP adherence and baseline PaCO2. Significantly greater improvements in gas exchange including a reduction in the need for daytime supplemental oxygen was seen with PAP use for > 6 h/night compared with less. These results reinforce the findings of a prior study showing the impact of adherence on PAP efficacy.17 Bouloukaki and colleagues showed similar improvements with both CPAP and bilevel PAP reinforcing the notion that more important than mode of PAP appears to be adherence to PAP therapy.10 It highlights the importance of close and regular follow-up of patients with OHS following initiation of PAP therapy to ensure optimal adherence. Additionally improvements in all measures including gas exchange, sleepiness, quality of life and depressive symptoms were associated with baseline values raising the question of whether treatment of isolated nocturnal hypercapnia would result in similar changes in clinical outcome. These two studies illustrate the need for additional long-term longitudinal studies exploring varying severities and phenotypes of OHS.
All authors have seen and approved the manuscript. The authors report no conflicts of interest.
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