PREDOMINANT OBSTRUCTIVE VERSUS PURE OBSTRUCTIVE APNEA 10.5665/SLEEP.1040 The Heterogeneity of Obstructive Sleep Apnea (Predominant Obstructive vs Pure Obstructive Apnea) Ailiang Xie, PhD2,3; Ajay Bedekar, MD1; James B. Skatrud, MD*1,3; Mihaela Teodorescu, MD1,3; Yuansheng Gong, PhD1; Jerome A. Dempsey, PhD2 1Department of Medicine, 2Population Health Sciences, University of Wisconsin, Madison, WI; 3Middleton Memorial Veterans Hospital, Madison, WI Study Objectives: To compare the breathing instability and upper airway collapsibility between patients with pure OSA (i.e. 100% of apneas are obstructive) and patients with predominant OSA (i.e., coexisting obstructive and central apneas). Design: A cross-sectional study with data scored by a fellow being blinded to the subjects’ classification. The results were compared between the 2 groups with unpaired student t-test. Downloaded from https://academic.oup.com/sleep/article/34/6/745/2656968 by guest on 24 September 2021 Setting and interventions: Standard polysomnography technique was used to document sleep-wake state. Ventilator in pressure support mode was used to introduce hypocapnic apnea during CO2 reserve measurement. CPAP with both positive and negative pressures was used to produce obstructive apnea during upper airway collapsibility measurement. Participants: 21 patients with OSA: 12 with coexisting central/mixed apneas and hypopneas (28% ± 6% of total), and 9 had pure OSA. Measurements: The upper airway collapsibility was measured by assessing the critical closing pressure (Pcrit). Breathing stability was assessed by measuring CO2 reserve (i.e., ∆PCO2 [eupnea-apnea threshold]) during NREM sleep. Results: There was no difference in Pcrit between the 2 groups (pure OSA vs. predominant OSA: 2.0 ± 0.4 vs. 2.7 ± 0.4 cm H2O, P = 0.27); but the CO2 reserve was significantly smaller in predominant OSA group (1.6 ± 0.7 mm Hg) than the pure OSA group (3.8 ± 0.6 mm Hg) (P = 0.02). Conclusions: The present data indicate that breathing stability rather than upper airway collapsibility distinguishes OSA patients with a combina- tion of obstructive and central events from those with pure OSA. Keywords: CO2 reserve, Pcrit, OSA Citation: Xie A; Bedekar A; Skatrud JB; Teodorescu M; Gong Y; Dempsey JA. The heterogeneity of obstructive sleep apnea ���������������������(predominant obstruc- tive vs pure obstructive apnea). SLEEP 2011;34(6):745-750. INTRODUCTION and respiratory control instability.2,6 On the other hand, when Since obstructive sleep apnea (OSA) is characterized by fu- the central respiratory output drops to zero, central apnea (CA) tile respiratory efforts against a closed upper airway, patients occurs regardless of UAW structural and functional status. It is with OSA are believed to have anatomical/functional deficits very likely that the phenotype of sleep apnea (CA vs. OA) is in the upper airway (UAW). However, patients very rarely shaped by the interaction of respiratory drive and UAW resis- present with pure OSA in clinical practice, with most OSA tance. We therefore hypothesized that for patients with equally patients exhibiting some proportion of central and/or mixed severe OSA, those with pure OSA have a more collapsible air- events. It is not clear why both types of apnea occur in the way than those with coexisting obstructive and central apneas same individual during the same night, but the coexistence of (predominant OSA); while the predominant OSA group have two types of apnea indicates more complicated underlying dis- more significant instability of the respiratory system than the orders than increased UAW resistance alone. In fact, unstable pure OSA group. To test this hypothesis, we measured CO2 breathing control has been implicated in the pathogenesis of reserve (i.e., ∆PCO2 [eupnea- apneic threshold]) to approxi- both central and obstructive sleep apnea. Some patients with mate the breathing propensity for instability and UAW critical OSA exhibit evidence of unstable ventilatory control (i.e., in- closing pressure (Pcrit) to assess the UAW collapsibility in pa- creased control system “loop gain,”) that could contribute to tients with OSA, and compared these 2 indexes between the 2 UAW narrowing and obstruction.1,2 We have noticed that ob- subgroups (pure OSA vs. predominant OSA). structive apnea (OA) begins at the nadir of respiratory drive,3 and that superimposing an unstable respiratory motor output METHODS precipitated airway obstruction during sleep in snoring sub- jects.4 We have also observed that increasing chemoreceptor Subjects stimulation (via increased inhalation of CO2) reduced UAW We studied 21 patients with OSA diagnosed via overnight resistance in sleeping subjects.5 Hence the occurrence of OA polysomnography (i.e. all patients had an apnea/hypopnea index appears to involve aspects of both upper airway collapsibility [AHI] > 10/h of sleep time). Of the apneas, ≥ 50% were classi- fied as obstructive in nature. Among these 21 subjects, 9 pre- sented with pure OSA (100% of apneas were obstructive) and Submitted for publication September, 2010 12 with predominant OSA (100% > obstructive apneas > 50%). Submitted in final revised form January, 2011 Subjects were excluded if they had chronic obstructive pulmo- Accepted for publication February, 2011 nary disease/asthma, concomitant medical illness such as renal/ *James Skatrud is deceased. liver dysfunction, or other confounding sleep disorders. All Address correspondence to: Ailiang Xie, MD, PhD, Pulmonary Physiology subjects provided informed consent prior to participation. The Laboratory, VA Hospital, 2500 Overlook Terrace, Madison, WI 53705; Tel: experimental protocol was approved by the University of Wis- (608) 256-1901, ext. 17544; Fax: (608) 280-7009; E-mail: [email protected] consin Center for Health Sciences Human Subjects Committee. SLEEP, Vol. 34, No. 6, 2011 745 Predominant Obstructive vs Pure Obstructive Apnea—Xie et al positive airway pressure (CPAP) to eliminate airway obstruction Table 1—Subject description and stabilize breathing. Then we administrated pressure support Pure OSA Predominant ventilation in a step-wise fashion by increasing the pressure by 2 group OSA group P-value cm H2O every 1 min until apnea and periodic breathing occurred. Number 9 (2 F + 7 M) 12 (1 F + 11 M) N/A et We confirmed this apneic threshold P CO2 by abruptly increas- Age, y 50.6 ± 3.8 54.1 ± 2.6 0.40 ing pressure to the previously determined level in one step. BMI, kg/m2 36.8 ± 2.8 34.3 ± 1.7 0.43 AHI, events/h 49.2 ± 9.4 47.1 ± 10.4 0.89 Upper Airway Critical Closing Pressure (Pcrit) AHI in NREM, events/h 45.9 ± 9.3 45.7 ± 9.4 0.75 Measurements of Pcrit were performed in a standard supine AHI in REM, events/h 57.0 ± 13.1 50.2 ± 16.3 0.77 posture with the head positioned in a contoured pillow to as- AHI in supine, events/h 51.4 ± 12.2 61.6 ± 16.1 0.64 sure a constant position. During stable NREM sleep, CPAP Obstructive apnea 27.7 ± 14.4 21.5 ± 7.0 0.67 was increased by 2 cm H2O every 1 min until flow limitation (% of total AH events) was eliminated, and this holding pressure was then maintained Downloaded from https://academic.oup.com/sleep/article/34/6/745/2656968 by guest on 24 September 2021 Central apnea 0 ± 0 11.4 ± 6.3 N/A throughout the study. For each trial, nasal pressure was lowered (% of total AH events) from the holding pressure by 1 cm H2O for 4-6 breaths and Mixed apnea 0 ± 0 11.8 ± 6.0 N/A then returned to holding pressure for 1 min before dropping to (% of total AH events) the next level. This sequence was repeated until airflow ceased (absolute Pcrit) or arousal occurred. Obstructive hypopnea 72.3 ± 14.4 50.6 ± 11.6 0.26 (% of total AH events) Data Analysis Central hypopnea 0 ± 0 4.7 ± 4.7 N/A For the CO reserve assessment, central apnea was defined (% of total AH events) 2 as absence of airflow and respiratory effort for ≥ 10 sec. The apnea threshold was determined by averaging the P CO of the BMI, body mass index; AHI, apnea-hypopnea index. ET 2 3 consecutive breaths immediately preceding the apnea.8 The difference between eupneic PETCO2 during stable breathing and The experiment was completed within 2 weeks following the the apneic threshold PETCO2 was calculated as the CO2 reserve. diagnostic study before the subjects received any treatment. All The absolute Pcrit was defined as the level of mask pressure patients reported to the laboratory in the evening, having re- at which inspiratory airflow first ceased. We were able to obtain frained from alcohol and caffeinated beverages during or after this in 18 of 21 subjects. In addition, in all subjects, we obtained their evening meal. Zolpidem 10 mg was given prior to bed to a derived Pcrit as determined from peak inspiratory flow-UAW facilitate sleep and to suppress the arousability from sleep for pressure relationships. Peak inspiratory flow of the 3rd through purpose of measuring Pcrit and apneic threshold. 5th breaths with unambiguous flow limitation during reduction in CPAP was averaged at each level of mask pressure. Pcrit was Experimental Set-Up derived by the zero-flow intercept from the least-square linear Subjects slept with a full face mask, through which they were regression of maximal flow vs. mask pressure as previously de- connected to a breathing circuit that could be directed to either a scribed.9 All data were collected only from flow-limited breaths positive pressure source (ventilator) (1~25 cm H2O) �������������or an adjust- with no associated arousal. able negative pressure source (-1~-10 cm H2O) from wall suction. Unpaired t-test was used for all of comparisons between the A 200 liter capacitance was placed in the inflow port to maintain 2 groups.