Noninvasive Ventilation in COPD. Impact of Inspiratory Pressure Levels on Sleep Quality

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1 CHEST Noninvasive Ventilation in COPD Original Research Impact of Inspiratory Pressure Levels on Sleep Quality CRITICAL CARE Michael Dreher, MD ; Emelie Ekkernkamp, MD ; Stephan Walterspacher, MD ; David Walker, MD ; Claudia Schmoor, PhD ; Jan H. Storre, MD ; and Wolfram Windisch, MD Background: Although high-intensity noninvasive positive pressure ventilation (HI-NPPV) is superior to low-intensity noninvasive positive pressure ventilation (LI-NPPV) in controlling nocturnal hypoventilation in stable hypercapnic patients with COPD, it produces higher amounts of air leakage, which, in turn, could impair sleep quality. Therefore, the present study assessed the difference in sleep quality during HI-NPPV and LI-NPPV. Methods: A randomized, controlled, crossover trial comparing sleep quality during HI-NPPV (mean inspiratory positive airway pressure 29 4 mbar) and LI-NPPV (mean inspiratory positive airway pressure 14 mbar) was performed in 17 stable hypercapnic patients with COPD who were already familiar with HI-NPPV. Results: Thirteen patients (mean FEV 1 27% 11% predicted) completed the trial; four patients refused to sleep under LI-NPPV. There was no significant difference in sleep quality between the treatment groups (all P..05), with a mean difference of 2 3.0% (95% CI, to 3.9; P 5.36) in the primary outcome, namely non-rapid eye movement sleep stages 3 and 4. However, nocturnal Pa CO 2 was lower during HI-NPPV compared with LI-NPPV, with a mean difference of mm Hg (95% CI, to 2 1.8; P 5.01). Conclusions: In patients with COPD, high inspiratory pressures used with long-term HI-NPPV produce acceptable sleep quality that is no worse than that produced by lower inspiratory pressures, which are more traditionally applied in conjunction with LI-NPPV. In addition, higher pressures are more successful in maintaining sufficient alveolar ventilation compared with low pressures. Thus, HI-NPPV is a very promising new approach, but still requires large, longer-term trials to determine the impact on outcomes such as exacerbation rates and longevity. Trial registry: German Clinical Trials Register (DRKS); No.: DRKS ; URL: CHEST 2011; 140(4): Abbreviations: HI-NPPV 5 high-intensity noninvasive positive pressure ventilation; IPAP 5 inspiratory positive airway pressure; LI-NPPV 5 low-intensity noninvasive positive pressure ventilation; NPPV 5 noninvasive positive pressure ventilation; NREM 5 non-rapid eye movement; ODI 5 oxygen desaturation index; REM 5 rapid eye movement; Sa o 2 5 arterial oxygen saturation; TLC 5 total lung capacity; TST 5 total sleep time Long-term noninvasive positive pressure ventilation (NPPV) in the home setting has become more widely used to treat chronic hypercapnic respiratory failure arising from different causes, and is most often applied during the overnight sleep period. 1 Although the survival benefits provided by long-term NPPV in individuals with restrictive thoracic disorders or stable, slowly progressing neuromuscular disorders are overwhelming, 2,3 the benefits provided by long-term NPPV in patients with COPD remain under question, because of a lack of convincing evidence in the literature. 4-8 In addition, long-term NPPV reportedly failed in the classic trials to improve important physiologic parameters, such as arterial blood gases, 7,8 which might serve as an explanation as to why long-term NPPV has not been shown to substantially impact on survival. However, high-intensity NPPV (HI-NPPV) using controlled NPPV with the highest possible inspiratory pressures tolerated by the patient has recently been described as a new and promising approach that is well tolerated and is also capable of improving important physiologic parameters, such as arterial blood gases and lung function This clearly contrasts with the conventional approach of low-intensity NPPV (LI-NPPV), which uses considerably lower inspiratory pressures with assisted forms of NPPV CHEST / 140 / 4 / OCTOBER,

2 Importantly, HI-NPPV was very recently shown to be superior to LI-NPPV in terms of improved overnight blood gases and was also better tolerated than LI-NPPV. Furthermore, HI-NPPV, but not LI-NPPV, improved dyspnea, lung function, and disease-specific aspects of health-related quality of life. 12 Therefore, there are justified reasons to speculate that the new technique of HI-NPPV can also improve long-term prognosis, and this needs to be verified by randomized controlled trials. Nevertheless, the most recent study despite its clear, positive results favoring HI-NPPV also demonstrated that the amount of air leakage is considerably higher compared with that associated with the conventional approach of LI-NPPV, 12 which could negatively impact on sleep quality. 13 On the other hand, sleep-related hypoventilation and hypoxemia are suggested to be the predominant conditions impacting on sleep quality in patients with severe COPD, 14 and this is superiorly handled by HI-NPPV. Therefore, it is necessary to comparably assess sleep quality during HI-NPPV and LI-NPPV. The present study, therefore, tested whether switching patients with COPD from HI-NPPV to LI-NPPV would result in improved sleep quality. A lack of improvement under these circumstances would strongly support the promising therapeutic role for long-term HI-NPPV in chronic hypercapnic patients with COPD. Thus, the current randomized crossover study comparably assessed sleep quality and overnight gas exchange during HI-NPPV and LI-NPPV in patients with COPD. Materials and Methods The study protocol was approved by the Ethics Committee at the Albert-Ludwigs University, Freiburg, Germany, and was performed in accordance with the ethical standards laid down in the Manuscript received January 31, 2011; revision accepted April 1, Affiliations: From the Department of Pneumology (Drs Dreher, Ekkernkamp, Walterspacher, Walker, Storre, and Windisch), and the Clinical Trials Unit (Dr Schmoor), University Medical Center, Freiburg, Germany. Drs Storre and Windisch contributed equally to this work. Funding/Support: The study was supported by the German Interdisciplinary Society of Home Mechanical Ventilation (Deutsche Interdisziplinäre Gesellschaft für Außerklinische Beatmung, DIGAB). The study group received an open research grant from Breas Medical AB (Molnlycke, Sweden), Respironics Inc (Pittsburgh, PA), and ResMed GmbH and Co KG (Germany ). Correspondence to: Michael Dreher, MD, Department of Pneumology, University Medical Center Freiburg, Killianstrasse 5, Freiburg, D-79106, Germany; michael.dreher@uniklinikfreiburg.de. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( site/misc/reprints.xhtml ). DOI: /chest Declaration of Helsinki. Informed, written consent was obtained from all subjects. Patients Patients with COPD with hypercapnic respiratory failure (stage IV GOLD [Global Initiative for Chronic Obstructive Lung Disease] criteria 15 ) and receiving appropriate medical therapy in addition to long-term oxygen therapy (according to GOLD guidelines 16 ) were included. All patients included in the study had been electively established on HI-NPPV during a stable phase of their disease prior to the study. Patients were examined during a routine control visit for NPPV and were not included in the study if they had acute respiratory failure (with two of the following criteria: increasing cough, purulent sputum, elevated leukocytes or C-reactive protein. 5 mg/dl, pulmonary infiltrates on chest radiograph, need for antibiotic treatment), received invasive ventilation via tracheostoma, were weaned from invasive ventilation, or were intubated during the last 3 months. Further exclusion criteria were bronchiectasis, post-tb sequelae, rib cage deformities, neuromuscular disorders, and bronchial carcinoma. Measurements Lung function parameters (Masterlab-Compact Labor; Jaeger; Hochberg, Germany) were assessed in accordance with international guidelines. 17 Arterial blood gases were taken from the arterialized earlobe (AVL OMNI; Roche Diagnostics GmbH; Graz, Austria) during oxygen therapy alone and during nocturnal NPPV in addition to supplemental oxygen, respectively. Full polysomnography (SOMNOscreen plus; Somnomedics GmbH; Randersacker, Germany) recorded abdominal and rib cage motion, arterial oxygen saturation (Sa o 2 ), ECG, electrooculograms, digastric electromyogram, bilateral anterior tibialis electromyogram, and EEG. Respiratory airflow was monitored with a pressure transducer connected to the mask. All variables were recorded continuously on a 12-channel EEG polygraph. Sa o 2 was continuously measured with a pulse oximeter and a finger probe. Minimum and mean Sa o 2, oxygen desaturation index (ODI) (transient desaturation defined as a decrease in Sa o 2 of 4%), number of desaturations, 90%, and the largest decrease in Sa o 2 were recorded. Sleep stage was classified according to international guidelines.18,19 Furthermore, the following sleep parameters were assessed: (1) total sleep time (TST); (2) sleep efficiency, defined as the TST divided by the time spent in bed; and (3) arousals, defined as the appearance on EEG of a waves that were 3 to 15 s in duration. 18 Sleep was scored according to the standard criteria using 30-s epochs. 18 The investigator scoring the sleep study was blinded to the ventilator settings and subjective evaluation. Techniques of NPPV Pressure-limited NPPV in assist/control mode together with supplemental oxygen was used in all patients for both treatment arms. Thereby, in order to establish controlled ventilation as previously detailed, 11,12 HI-NPPV was aimed at maximally decreasing Pa co 2 by means of stepwise increases in inspiratory positive airway pressure (IPAP) and respiratory rate beyond the spontaneous breathing frequency. For LI-NPPV, IPAP was set to 14 mbar, without changing any other ventilatory parameters (eg, expiratory positive airway pressure, respiratory rate, ventilation mode, and so forth). IPAP implies the absolute value without adding expiratory pressure. Commercially available nasal or oronasal masks were used for NPPV. A heat and moisture exchanger (Hygrovent S, Medisize bv; Hillegom, The Netherlands) was provided for passive humidification if patients complained about airway dryness. 940 Original Research

3 Study Design The study had a randomized, open-label, two-treatment, twoperiod crossover design. All patients were studied for a total of two consecutive nights. Patients were randomized to receive either the HI-NPPV/LI-NPPV sequence or the LI-NPPV/HI-NPPV sequence during nocturnal ventilation. Full polysomnography was performed during both nights and arterial blood gases were taken at 2:00 am. After the first night, patients were switched to the alternative mode of NPPV. The study was performed as a single-center study at the Department of Pneumology, University Medical Center Freiburg, Germany. Statistical Analysis The primary end point was slow-wave sleep (non-rapid eye movement [NREM] stages 3 and 4) during nocturnal NPPV, measured as the % of TST used for sample size calculation. The study was designed to show a difference between LI-NPPV and HI-NPPV in NREM stages 3 and 4 of 10% TST. For the SD of the difference, a value of 10% TST was assumed according to previous findings. 20 Based on these assumptions, the recruitment of 13 patients was required to show a difference using a crossover design with a two-sided significance level of 0.05 and a power of The comparison of LI-NPPV and HI-NPPV was performed in the full analysis set, which included all randomized patients who received both treatments in the crossover setting. Analysis of variance models were used based on the assumption that the data were normally distributed. Treatment, period, and randomized sequence were defined as fixed effects, whereas patient within sequence was defined as a random effect. The treatment effect was estimated as the difference in HI-NPPV vs LI-NPPV, with 95% CI, and tested with a two-sided level of For description of the data, mean SD is shown per treatment and per period. For the end points apnea-hypopnea index scores, ODI, Sa o 2, 90%, and largest decrease in Sa o 2, the assumption of normal distribution appeared to be unfulfilled. These data were thus included in the analysis of variance models after log transformation. The treatment effect was estimated as the ratio of HI-NPPV vs LI-NPPV, with 95% CI; median and quartiles are shown per treatment and per period. In addition, tests for period and carryover effects (ie, treatmentperiod interactions) were performed, and generally showed no relevant effects. The test for carryover showed a P value,.01 only in the single case of mean Sa o 2 (ie, the treatment effect seemed to differ between periods). Results Seventeen patients were consecutively enrolled in the study. Four patients dropped out ( Fig 1 ). One patient in period one and three patients in period two refused to sleep under LI-NPPV because of fear of asphyxia. Data are presented for the full analysis set consisting of the 13 patients who completed both treatments in the crossover setting. Demographic data, ventilator settings for HI-NPPV, lung function parameters, and daytime blood gases with supplemental oxygen are shown in Table 1. Mean duration of home mechanical ventilation was months. NPPV was applied using BREAS PV401 (n 5 1), PV403 (n 5 1), and VIVO 30 (n 5 6) and VIVO 40 (n 5 5) (Breas Medical AB; Molnlycke, Figure 1. Trial profile. ABG 5 arterial blood gases; NPPV 5 noninvasive positive pressure ventilation. Sweden). Eight patients used a nasal mask, and five patients used an oronasal mask. There was no significant difference between HI-NPPV and LI-NPPV in terms of the primary end point, namely, slow-wave sleep (NREM stages 3 and 4), with a mean difference of only 2 3.0% (95% CI, to 3.9; P 5.36). Furthermore, no differences were seen in overall sleep quality and nocturnal heart rates when HI-NPPV was compared with LI-NPPV ( Fig 2, Table 2 ). Nocturnal Pa co 2 was lower during HI-NPPV compared with LI-NPPV, with a treatment effect of mm Hg (95% CI, to 2 1.8; P 5.01) ( Fig 3 ). Consequently, ph was higher during HI-NPPV compared with LI-NPPV Table 1 Demographic Data, Ventilator Settings for HI-NPPV, Lung Function Parameters, and Daytime Blood Gases During Spontaneous Breathing With Supplemental Oxygen Characteristic Mean SD Age, y BMI, kg/m IPAP, mbar EPAP, mbar Bf, /min Inspiratory time, s Mean oxygen flow rate, L/min FVC, % pred FEV 1, % pred FEV 1 /FVC, % TLC, % pred RV, % pred Pa o 2, mm Hg Pa co 2, mm Hg ph Bf 5 breathing frequency; EPAP 5 expiratory positive airway pressure; HI-NPPV 5 high-intensity noninvasive positive pressure ventilation; IPAP 5 inspiratory positive airway pressure; Pa co 2 5 arterial partial pressure of carbon dioxide; Pa o 2 5 arterial partial pressure of oxygen; RV 5 residual volume; TLC 5 total lung capacity. CHEST / 140 / 4 / OCTOBER,

4 (76% 16%); NREM stage 1, 20% 13% (17% 11%); NREM stage 2, 48% 16% (50% 17%); NREM stages 3 and 4, 15% 6% (18% 13%), and rapid eye movement (REM), 16% 8% (15% 9%) (Fig 2 ). Discussion Figure 2. Sleep (mean SD) during HI-NPPV and LI-NPPV with a sleep efficiency of 80.0% 15.9% during HI-NPPV and 75.8% 16.4% during LI-NPPV. HI-NPPV 5 high-intensity noninvasive positive pressure ventilation; LI-NPPV 5 low-intensity noninvasive positive pressure ventilation; NREM 5 nonrapid eye movement sleep. ( P 5.03), and bicarbonate was lower ( P 5.013) ( Table 3 ). Furthermore, three patients were normocapnic (Pa co 2, 45 mm Hg), and four patients had only mild hypercapnia (Pa co mm Hg) during HI-NPPV compared with one and two patients, respectively, during LI-NPPV. Descriptive sleep quality data during HI-NPPV (LI-NPPV) are as follows: sleep efficiency, 80% 16% This is the first randomized crossover trial, to our knowledge, to compare the effects of different forms of NPPV (HI-NPPV vs LI-NPPV) on sleep quality in patients with chronic hypercapnic respiratory failure due to COPD. Two main findings are reported and discussed. First, sleep quality was comparable between HI-NPPV and LI-NPPV. This also pertained to arousals, suggesting that a reduction in IPAP does not result in an improvement in sleep quality. Although the most recently published trial that directly compared both modes did not objectively measure sleep quality, there was indirect evidence to suggest that sleep quality was not compromised during HI-NPPV, since subjective aspects of sleep quality did not differ between HI-NPPV and LI-NPPV. 12 Therefore, higher inspiratory pressures obviously do not worsen sleep quality compared with lower pressures when used for NPPV in patients with COPD. There is no doubt that sleep quality is compromised in patients with COPD, who experience a Table 2 Polysomnographic Measurements During Nocturnal Noninvasive Ventilation, HI-NPPV vs LI-NPPV Measure Period LI-NPPV HI-NPPV Treatment Effect (95% CI) P Value NREM stages 3 and 4, % TST ( 210.0, 3.9) TST, min ( 234, 101) Sleep efficiency, % ( 23.6, 11.6) NREM stage 1, % TST ( 25.8, 11.5) NREM stage 2, % TST ( 215.0, 10.9) REM sleep, % TST ( 24.0, 6.6) Arousals, No./h ( 28.8, 9.3) AHI score, a events/h (0/24.5) 0.7 (0/6.7) (0.9/4.1) 1.9 (1.1/5.1) (0.42, 1.27) Mean heart rate, /min ( 25.2, 0.8) Maximal heart rate, /min ( 29.1, 21.2) SD heart rate ( 20.23, 1.59) Data are presented as mean SD unless otherwise noted. Period 1 and period 2 refer to the sequential treatment periods each patient received in the crossover design (see Fig 1 ). AHI 5 apnea-hypopnea index; LI-NPPV 5 low-intensity noninvasive positive pressure ventilation; NREM 5 nonrapid eye movement; REM 5 rapid eye movement; TST 5 total sleep time. See Table 1 for expansion of other abbreviation. a Included in the analysis of variance models after log transformation. Treatment effect as estimated by the ratio of HI-NPPV vs LI-NPPV, with 95% CI. For descriptive purposes, median and quartiles are shown per treatment and per period. 942 Original Research

5 Figure 3. Nocturnal (mean SD) Paco 2 during HI-NPPV and LI-NPPV. See Figure 2 legend for expansion of abbreviations. reduction in both sleep efficiency and TST, a delay in sleep onset, and frequent, prolonged periods of wakefulness. 21 Sleep quality was reportedly improved when LI-NPPV was prospectively used in several randomized controlled trials. 4,22,23 On the other hand, no sleep quality-related benefits gained from LI-NPPV have been reported in other studies Nevertheless, in order to grant HI-NPPV its promising role in the treatment of chronic hypercapnic respiratory failure in patients with COPD, sleep quality must at least be shown to be no worse during HI-NPPV than during LI-NPPV. In the present study, sleep quality during HI-NPPV was acceptable and not particularly worse than that reported by previous studies using LI-NPPV. 22,23 In addition, two further trials have also demonstrated acceptable sleep quality during HI-NPPV 27,28 and are comparable to the current study. Furthermore, sleep quality during HI-NPPV in the present study was comparable to sleep quality previously assessed in patients with mild COPD. 29 Thus, the current study confirms the previous finding of acceptable sleep quality assessed during HI-NPPV, which was no worse than sleep quality assessed during LI-NPPV. Second, a reduction in IPAP resulted in worsening of nocturnal hypoventilation as reflected by a significant increase of 6 mm Hg in nocturnal Pa co 2 accompanied by a drop in ph. Therefore, the present study clearly showed for the first time that IPAP is the major determinant for maintaining alveolar ventilation, since the underlying ventilator mode and breathing frequency remained unchanged. It might be speculated that additionally reducing the breathing frequency would have resulted in further deterioration of alveolar ventilation, an assumption supported by recent research showing an even higher mean difference of 9 mm Hg in nocturnal Pa co 2 between HI-NPPV and LI-NPPV, when both IPAP and breathing frequencies were considerably reduced during LI-NPPV. 12 Nevertheless, this study undoubtedly confirms that an optimal alveolar ventilation status can only be achieved by HI-NPPV with a mean IPAP of nearly 30 mbar. The current study has two limitations that need to be addressed. First, patients were already under treatment with HI-NPPV but were naive to LI-NPPV Table 3 Measurements of Sa O 2 and Blood Gases During Nocturnal Noninvasive Ventilation, HI-NPPV vs LI-NPPV Measure Period LI-NPPV HI-NPPV Treatment Effect (95% CI) P Value Mean Sa o 2, % ( 21.1, 3.7) Minimum Sa o 2, % ( 21.6, 6.9) ODI, events/h a (0.5/26.0) 1.1 (0.6/5.9) (0.9/3.8) 1.9 (0.6/5.1) (0.43, 1.34) Sa o 2, 90%, No. a (2/111) 2.5 (1/11) (0/3) 6.0 (0/14) (0.38, 1.92) Largest decrease in Sa o 2, % a (5/14) 5.5 (4/9) (4/6) 7.0 (4/13) (0.63, 1.67) ph (0.004, 0.046) Pa o 2, mm Hg ( 24.7, 9.8) Pa co 2, mm Hg ( 210.9, 21.8) HCO 2 3, mmol/l ( 23.1, 20.5) Data are presented as mean SD unless otherwise noted. Period 1 and period 2 refer to the sequential treatment periods each patient received in the cross-over design (see Fig 1 ) HCO bicarbonate; ODI 5 oxygen desaturation index; Sa o 2 5 arterial oxygen saturation. See Tables 1 and 2 legends for expansion of other abbreviations. a Included in the analysis of variance models after log transformation. Treatment effect as estimated by the ratio of HI-NPPV vs LI-NPPV, with 95% CI. For descriptive purposes, median and quartiles are shown per treatment and per period. CHEST / 140 / 4 / OCTOBER,

6 when entering the study. Therefore, it cannot be excluded with certainty that sleep quality would have improved if patients had had the chance to become further acclimatized to LI-NPPV. However, this is very unlikely based on the observation that sleep quality during LI-NPPV was comparable to that reported in all previous trials. 22,23 In contrast, HI-NPPV was better tolerated than LI-NPPV, since patients only dropped out during the LI-NPPV phase, both in the present and most recent trial. 12 Second, the LI-NPPV used in the present study was not directly comparable to either the most recent trial 12 or to the majority of previous trials, 5-7 as breathing frequencies during LI-NPPV were not reduced but rather similar to the breathing frequencies recorded during HI-NPPV with controlled ventilation; this might theoretically complicate comparisons with previous studies. In conclusion, HI-NPPV used in a controlled mode with a mean inspiratory positive airway pressure of 29 mbar is associated with acceptable sleep quality, which is similar rather than reduced in comparison with LI-NPPV. Furthermore, HI-NPPV is superior in controlling nocturnal hypoventilation compared with LI-NPPV. HI-NPPV is a very promising new approach for treating stable hypercapnic patients with COPD; however, an important question remains: Is high-intensity NPPV also capable of improving long-term survival? To address this, long-term randomized controlled trials are urgently needed. Acknowledgments Author contributions : Dr Dreher: contributed to the planning, data collection, data analysis, and writing of the manuscript. Dr Ekkernkamp: contributed to the data collection and writing of the manuscript. Dr Walterspacher: contributed to the data collection and writing of the manuscript. Dr Walker: contributed to the data collection and writing of the manuscript. Dr Schmoor: contributed to the statistical analysis of the data and writing of the manuscript. Dr Storre: contributed to the data collection, data analysis, and writing of the manuscript. Dr Windisch: contributed to the data analysis and writing of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Dreher has received speaking fees from VitalAire, ResMed, Drager Medical, and Respironics. Dr Walterspacher has received travel grants from Vivosol and speaking fees for discussions on BiPAP. Dr Walker has received travel grants from Vivosol. Dr Storre received speaking fees from Heinen und Lowentsein, Werner und Muller Medizintechnik, and Respironics; and honorarium from Respironics for expertise. Travel funding for national and international research congresses was supplied by Breas Medical GmbH, Respironics International, Respironics, Sentec AG, Vivisol, Weinmmann GmbH, and Werner und Muller Medizinechnik. Dr Windisch received research grants from Respironics and Breas. He received speaking fees from Drager Medical, Heinen und Lowenstein, VitalAire, Respironics, ResMed, MPV Truma, Covidien, Linde, and Siare. Drs Ekkernkamp and Schmoor have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors had no role in the study design, results, interpretation of the findings, or any other subject discussed in the submitted manuscript. Other contributions: We thank Sandra Dieni, PhD, for helpful comments on the manuscript prior to submission. References 1. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation a consensus conference report. Chest ;116(2): Simonds AK, Elliott MW. 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