STUDY OBJECTIVES:Medium and long-term trials comparing continuous positive airway pressure (CPAP) with noninvasive ventilation in patients with obesity hypoventilation syndrome have shown no differences in outcomes. However, it remains unclear whether CPAP therapy should be prescribed if significant hypoxemia persists during CPAP titration, despite optimization of upper airway obstructive events or if maximum CPAP pressure is reached. We aimed to examine the effects of 6 weeks of home CPAP therapy on gas exchange in patients with obesity hypoventilation syndrome who failed CPAP titration due to persistent hypoxemia. METHODS:This case series is a substudy of a randomized-controlled trial evaluating efficacy of 3 different PAP modalities in obesity hypoventilation syndrome. Patients randomized to CPAP who failed titration and were prescribed CPAP are included. CPAP failure was defined as spending more than 20% of total sleep time with oxygen saturation below 90% despite adequate resolution of apneas and hypopneas. Follow-up data included in-laboratory polysomnogram on prescribed CPAP after 6 weeks of home CPAP therapy. RESULTS:Three of seven participants (43%) randomized to CPAP failed CPAP titration. All were morbidly obese, had severe OSA (apnea-hypopnea index > 90 events/h) and severe sleep hypoxemia (percentage of total sleep time with oxygen saturation < 90% [T90] = 60-89%). Hypoxemia (T90: 43-67%, T80: 0-31%, and T70: 0-11%) and hypercapnia (transcutaneous pressure of CO₂ levels > 50 mm Hg) persisted during CPAP titration polysomnogram. The final polysomnogram after 6 weeks of adherent home CPAP therapy showed effective control of obstructive sleep apnea. Hypoventilation and hypoxemia severity decreased significantly in all 3 participants. CONCLUSIONS:Our data suggest that CPAP titration failure does not equal CPAP treatment failure. CLINICAL TRIAL REGISTRATION:Registry: ClinicalTrials.gov; Name: AVAPS-AE Efficacy Study; URL: https://clinicaltrials.gov/ct2/show/NCT01368614; Identifier: NCT01368614.