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Effects of volume-assured pressure support noninvasive ventilation in stable COPD with chronic respiratory failure: Meta-analysis and literature review
ARTICLE IN PRESS Heart & Lung 000 (2020) 19
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Effects of volume-assured pressure support noninvasive ventilation in stable COPD with chronic respiratory failure: Meta-analysis and literature review Xiaomin Zhangc, Piaoyu Yanga, Chengyao Guoc, Shanqun Lib,**, Yuxia Zhanga,* a
Department of Nursing, Zhongshan Hospital, Fudan University, Shanghai, 200032, China Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China c Nursing School, Fudan University, Shanghai, 200032, China b
A R T I C L E
I N F O
Article History: Received 9 September 2019 Revised 13 January 2020 Accepted 22 January 2020 Available online xxx Keywords: Volume-assured pressure support Noninvasive positive pressure ventilation Chronic obstructive pulmonary disease Sleep Quality of life
A B S T R A C T
Background: Patients receiving long-term home noninvasive ventilation (NIV) may slow down the progression to acute exacerbation of chronic obstructive pulmonary disease (AECOPD), however, the problem with respiratory instability during sleep diminished was persisted, which may reduce the effectiveness of NIV and the patient’s quality of life. A novel NIV mode with volume-assured pressure support (VAPS) has been gradually applied to improve sleep quality in COPD patients with chronic respiratory failure. This meta-analysis aimed to evaluate the efficacy of VAPS in stable COPD patients with chronic respiratory failure. Methods: We performed an electronic literature search for RCTs from January 2008 to October 2018. Studies investigating the effects of VAPS in stable COPD patients with chronic respiratory failure were conducted, and the following primary outcomes were reviewed: effectiveness of ventilation, sleep quality, and quality of life. Results: Five studies with 150 subjects were identified. While questionnaire scores showed significant improvements in the VAPS mode, no significant difference was found in the effectiveness of ventilation (pH, MD = 0.01 [95% CI -0.01 to 0.02, P = 0.27]; PaCO2, MD = 1.25 [95% CI -1.45 to 3.95, P = 0.37]; PaO2, MD = 3.14 [95% CI -0.76 to 7.05, P = 0.11]; mSaO2, MD = 0.23 [95% CI -1.22 to 1.67, P = 0.76]; mPtcCO2, MD = 3.03 [95% CI -6.06 to- 0.60, P = 0.10]). The VAPS mode did not seem to ameliorate sleep quality and quality of life. Conclusion: The VAPS mode had similar efficacy as the pressure-support (PS) mode. However, VAPS could significantly improve the patients’ subjective feelings. © 2020 Elsevier Inc. All rights reserved.
Introduction Chronic obstructive pulmonary disease (COPD) is a leading but underestimated cause of mortality worldwide that is predicted to move from the fourth to third position in terms of morbidity during 19902020, just behind ischemic heart disease and stroke worldwide,1 and from the sixth to third position as the most common cause of death.2 COPD is a common disease characterized by recurrent respiratory symptoms and persistent airflow limitation.1 Along with progressive aggravation, COPD patients show a high risk of relapse. With the increase in the number of smokers in developing countries and the aging population in developed countries, the number of
* Corresponding author: Yuxia Zhang, Department of Nursing, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China, 200032. ** Shanqun Li, Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China, 200032. E-mail addresses: [email protected] (S. Li), [email protected] (Y. Zhang). https://doi.org/10.1016/j.hrtlng.2020.01.007 0147-9563/© 2020 Elsevier Inc. All rights reserved.
COPD patients is increasing.2 COPD results in a decline in the quality of life and increasing social and financial burdens. Moreover, as the disease progresses, patients with moderate to severe COPD are prone to show respiratory failure. The GOLD 2019 report1 noted that patients with persistent daytime hypercapnia could benefit from noninvasive positive pressure ventilation (NIPPV), which has been used worldwide for patients with acute or chronic respiratory failure in recent years.35 Several studies6,7 have suggested that NIPPV is likely to play an important role in intensive care units (ICUs). It could reduce the length of ICU stays and the incidence of pneumonia. In 2017, a meta-analysis8 suggested that NIPPV could improve the partial pressure of arterial oxygen (PaO2) in COPD patients with stable hypercapnia, and found that COPD patients could benefit from the high-pressure mode of NIPPV.9 NIPPV can be divided into two types10: pressure- or volume-control mode. Currently, continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) use the pressure-control (PS) mode.11 Higher pressures can cause respiratory muscle fatigue and
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increase the incidence of dyspnea in COPD patients, so physicians should chose the ventilation mode carefully. Meanwhile, a metaanalysis showed that while NIPPV could improve PaCO2 over the short term, it did not show any significant long-term effectiveness in alleviating dyspnea and promoting daily activity levels.12 Therefore, identification of an appropriate ventilation mode is crucial. BiPAP provides two levels of pressure: an inspiratory positive airway pressure (IPAP) and a lower expiratory positive airway pressure (EPAP), which increase the patient's inspiratory depth and the quantity of inhaled air and improve auxiliary ventilation. However, the disadvantage is that once the air leaks, it will greatly interfere with the patient-machine synchronization. CPAP machines were initially used mainly by patients for treatment of sleep apnea at home, but they are now widely used in intensive care units. The pressure in the CPAP mode is too high for patients to tolerate for long periods of time. However, many studies have also shown that the pressure- or volume-control modes have their unique advantages.13,14 For instance, the pressure-control mode can be adjusted according to the peak inspiration pressure of the patient, thus increasing patient comfort15; similarly, the volume-control mode can guarantee an effective tidal volume in the minimum ventilation time.16 These unique advantages indicate the need for a mixed volume and pressure mode. Combining the advantages of these two modes, volume-assured pressure support (VAPS), a hybrid mode, measures the target volume based on the patient's characteristics, such as the degree of airway restriction, patient coordination, and the ability to automatically regulate peak inspiration and expiratory pressure.17 Several recent RCTs have compared the effectiveness of VAPS with BiPAP in stable COPD patients with respiratory failure and shown that the ventilation outcomes were better in the VAPS group. Coughlin et al.18 indicated that VAPS could decrease readmissions and relieve the resultant financial burden. However, since these studies had some limitations, including short intervention times and small sample sizes, the application of VAPS is worth further investigation. Therefore, we have evaluated the impact of the VAPS mode in stable COPD patients with respiratory failure, including assessment of efficacy of ventilation, sleep quality, and quality of life. Methods Search strategy We conducted a comprehensive assessment by searching the Cochrane Library, CINAHL, EMBASE, PubMed, and Web of Science for RCTs with human participants from the establishment of the database to September 2018; meeting abstracts and "gray" literature were excluded from the search. The following medical subject heading (MeSH) terms were used as key words: “Pulmonary Disease, Chronic Obstructive,” “volume assured pressure support,” “volume targeted pressure support,” and “volume limited pressure support.” The literature search was conducted independently by two reviewers (ZHANG and YANG). The search strategy for PubMed is shown in Appendix 1. Inclusion and exclusion criteria The included studies met the following criteria: (1) patients with COPD GOLD stage III or IV (forced expiratory volume in 1 second (FEV1)/forced vital capacity < 70% and FEV1 < 50% predicted); (2) patient age between 40 and 76 years with stable clinical condition (no exacerbation in the four weeks prior to study participation together with a pH > 7.35); (3) a history of chronic hypercapnic respiratory failure (an arterial carbon dioxide pressure (PaCO2) > 6.0 kPa at rest while breathing room air); (4) VAPS mode used in the intervention group, and volume- or pressure control used
in the control group; and (5) an RCT design and publication in English. Studies were screened independently by the two reviewers. Data extraction and quality assessment An approach based on the Cochrane Risk of Bias 2014 RCT evaluation tool was used. A risk of bias assessment of the included studies was separately performed by two reviewers (ZHANG and GUO). Divergences between the two reviewers in specific studies were settled by the third reviewer (YANG). The data were extracted by the reviewer ZHANG, and the following study characteristics were collected: study ID, patient characteristics, sample size, study design (intervention and control measures), and outcome. The results of data extraction were verified by the reviewer YANG. Statistical analysis The mean difference (MD) was selected while estimating the total effect of continuous variables. Next, the standardized mean difference (SMD) was selected while combining outcomes measured on different scales by listing them based on their standard deviations. Heterogeneity was tested and significance was set at P < 0.05. We used the fixed model if there was low heterogeneity, and the metaanalyses findings that could not be evaluated due to significant heterogeneity were reported narratively. We used Review Manager 5.3 to pool the results and assess the treatment efficacy. Both the pooled effects and 95% confidence intervals (CIs) were calculated. Forest plots were used to display the results visually, and funnel plots were used to describe publication bias. Results Search results The process of study selection is shown in Fig. 1. A total of 241 studies were retrieved through the database searches. Among these, five eligible studies1923 with 150 subjects were included in this meta-analysis: one was an RCT and the remaining four were randomized crossover studies. Characteristics of the included studies The “characteristics of the included studies” table presents detailed descriptions of the methods, participants, interventions, and outcomes (Table 1). Characteristics of excluded studies The reasons for excluding studies were provided by the reviewers, and they included incompatible study type (n = 89), use of non-volume- and pressure-control mode (n = 33), and a disease type that did not meet the inclusion criteria (n = 35). After assessment of the full text of the articles, eight were excluded, with four articles assessing a mixture of COPD patients and those showing asthma, obstructive sleep apnea (OSA), or kyphoscoliosis; two articles assessing a mixed VAPS mode with PS mode in the intervention; and two studies for which the full text could not be obtained limited for language. Risk of bias in the included studies A graphical overview of our assessments for the six standards, namely, selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias, is provided in Fig. 2. All studies had clearly described the randomization process. Three studies used appropriate allocation and concealment methods and
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Fig. 1. Study flow diagram. Search performed in October 2018.
two reported that the participants were blinded for the interventions. However, only one study reported blinding of the outcome assessment: three studies had a high risk of incomplete outcome, and most studies had a low risk of reporting bias and other bias.
in favor of the experimental group, which was not significant (95% CI 1.38 to 6.00, Analysis 1.3). Thus, the result shows stabilization.
Effects of the intervention
Four of the five trials assessed this outcome in a total of 55 participants in the experimental group and 55 in the control group. The common effect (mean difference) in power was 3.14 in favor of the control group, which was not significant (95% CI 0.76 to 7.05, Analysis 1.4).
Efficacy of ventilation Arterial blood gas (ABG) was most widely used index to show the efficacy of ventilation, which also included assessments of post-procedure pH, PaCO2, PaO2, etc. Meanwhile, minute ventilation (VE) was also used frequently. pH Three of the five trials included this outcome: a total of 35 s participants in the experimental group and 35 in the control group. The common effect (mean difference) in power was 0.01 in favor of the control group (95% CI 0.01 to 0.02, Analysis 1.1). PaCO2 Four studies measured the PaCO2 in a total of 55 participants in the experimental group and 55 in the control group. The common effect (mean difference) in power was 1.25 in favor of the experimental group (95% CI 1.45 to 3.95, Analysis 1.2). However, the forest plot shows that one study24 had a high weight. Therefore, we removed that study from sensitivity analysis. As a result, the power was 2.31
PaO2
mSaO2 Three trials assessed this outcome in a total of 52 participants in the experimental group and 52 in the control group. The common effect (mean difference) in power was 0.23 in favor of the control group, which was not significant (95% CI 1.22 to 1.67, Analysis 1.5). mPtcCO2 Four trials assessed this outcome in a total of 66 participants in the experimental group and 66 in the control group. The common effect (mean difference) in power was 3.39 in favor of the control group (95% CI 6.05 to- 0.73, Analysis 1.6). However, we found that the study26 had a high weight, so we removed that study from sensitivity analysis. As a result, power was 3.03 in favor of the control group, which did not show statistical significance (P = 0.10, Analysis 1.7).
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X. Zhang et al. / Heart & Lung 00 (2020) 19 Table 1 Characteristics of the included studies. Sample
Design
I
C
Intervention
Control
Outcomes
Ernesto Crisafulli 2009
Stable COPD 9
9
- IPAP was set at the patient’s maximal tolerated level (up to 30 cmH2O). 5-day periods
①②③⑨⑪⑫
Nichholas S. Oscroft 2010
Stable COPD 12
12
Stable COPD 20
20
Emelie Ekkernkamp 2014
Stable COPD 14
14
-The inspiratory trigger was left in the default setting and cycling to expiration was at 25% of the maximal inspiratory flow. 8 weeks - The expiratory pressure was set at 5 cmH20 and the inspiratory pressures were increased and inspiratory time and backup rate adjusted to optimize ventilation with the aim of reducing PtcCO2 3 months -Established on effective ventilation
①②③④⑤⑥⑦⑧⑩
Nichholas S. Oscroft 2014
-Target tidal volume was set to 8 ml/kg of the patient’s ideal body weight -IPAP ranging from EPAP up to 30 cmH2O - 5-day period -Yielded an average figure of minute ventilation that was adopted as the TgV - Adjustment of inspiratory pressure up to 25 cm H2O 8 weeks - Recorded the minute ventilation and respiratory rate -Attempted to reproduce TgV overnight automatically by adjusting the inspiratory pressures in the range of 725 cmH2O. 3 months - Established on effective ventilation, combined pressure-support ventilation with TgV -Quickly adjusted when the ventilation was below the target ventilation 6 weeks -iVAPS: adjusted to reduce pCO2 to 50 mmHg, measured by capillary blood samples in the morning about 1 h after the end of nocturnal ventilation -Inspiratory pressure was increased gradually. 1 night
Study
Patients
Gerog Nilius 2017
Stable COPD 20
20
②③④⑤⑥⑦⑧
①②③⑤⑩⑫
-Ventilators and ventilator settings were not changed 6 weeks -ST: adjusted to reduce pCO2 to 50 mmHg, ④⑤⑪⑫ measured by capillary blood samples in the morning about 1 h after the end of nocturnal ventilation -Inspiratory pressure was increased gradually. 1night
①pH②PaCO2③PaO2④mSaO2⑤ mPtcCO2⑥ SWT⑦ SF-36⑧ SGRQ⑨VE⑩VAS⑪ Sleep questionnaire ⑫ PSG Abbreviations: IPAP: inspiratory positive airway pressure; EPAP: expiratory positive airway pressure, TgV: target minute ventilation, PaO2: partial pressure of arterial oxygen; PaCO2: partial pressure of arterial carbon dioxide, VAS: visual analog scale, SGRQ: St George’s Respiratory Questionnaire, SWT: shuttle walk test, VE: minute ventilation, mPtcCO2: Mean nocturnal PtcCO2, mSaO2: Mean nocturnal SaO2, PSG: polysomnography, SF-36: short form 36, PIP: Peak inspiratory pressure.
Minute ventilation Minute ventilation was measured in one of the five trials. In this trial, where 9 participants in the VAPS group were compared to 9 participants in the control group, the result showed that differences in minute ventilation between groups did not have statistical significance. Effects on sleep Polysomnography PSG as a sensitive indicator of sleep monitoring was performed in two clinical trials. PSG records the total sleep time, sleep efficiency, N1 sleep, N2 sleep, N3/4 sleep, REM sleep, etc. In one trial,21 14 participants in the iVAPS group were compared to 14 participants in the control group with no significant difference. In other trials, where 20 participants in the iVAPS group were compared to 20 participants in the control group, apart from sleep efficiency (TST/time in bed), which was slightly higher in the iVAPS group than in the pressurecontrolled mode group (p = 0.056), no other parameter showed significance.23
sleep, morning freshness, pressure-included discomfort, and mask fit and found that the differences in the comfort level were significant, and the patients in iVAPS group were more comfortable. Sleep questionnaire Two studies19,23 used sleep questionnaires to measure sleep quality. One trial used a ten-item questionnaire (score 010, with 10 corresponding to the worst sleep quality) and found that the AVAPS group showed more efficient sleep. Another trial used a five-item questionnaire (score 05, where a lower score indicated better acceptability), and the results showed no significant statistical differences between the two ventilation modes (p = 0.142). Health-related quality of life Two studies20,22 investigated the effect of VAPS on the HRQL by evaluating the SF-36, St George’s Respiratory Questionnaire (SGRQ), and shuttle walk test (SWT). The follow-up time of one trial20 was 8 weeks, and the difference did not show significance. The follow-up time of the other trial20 was three months, and there were significant improvements in total SGRQ and SF-36 emotional summary scores in the VAPS group.
Visual analogue scale Discussion The visual analogue scale (VAS) is used to assess the sleep quality associated with the ventilators. Three trials measured VAS. One trial19 only showed that the comfort level significantly improved with ventilation. Another clinical trial20 showed improvements in usage, tolerability, comfort level, and sleep quality, but no significant difference in VAS scores. The third study recorded the restfulness of
Summary of the main results VAPS, including AVAPS and iVAPS, is a hybrid-ventilation mode, but its principle is still based on pressure support. There are compelling data showing that VAPS had significant therapeutic effects
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Fig. 2. Database search (n = 241)PubMed = (6), EMBASE = (38), MEDLINE = (14), CINAHL = (6), Cochrane Library = (125),Web of Science = (52)173 records after removing duplicates (241 - 68 = 173)13 records after reading title/abstracts160 records excludedP (patients):35I (intervention):33O (outcome):3S (study): 895 records after reading the full text8 texts excludedP: 4 included other diseases, such as OSAI: 2 used VAPS+PSLanguage: 2 Database search (n = 241)PubMed = (6), EMBASE = (38), MEDLINE = (14), CINAHL = (6), Cochrane Library = (125),Web of Science = (52)173 records after removing duplicates (241 - 68 = 173)13 records after reading title/abstracts160 records excludedP (patients):35I (intervention):33O (outcome):3S (study): 895 records after reading the full text8 texts excludedP: 4 included other diseases, such as OSAI: 2 used VAPS+PSLanguage: 2 Fig. “Risk of bias” summary: review of authors’ judgements for each risk of bias item in each included study.
against hypoventilation with or without obesity in patients with chronic or acute hypercapnia respiratory failure caused by OSA and kyphoscoliosis,24 but our study found that patients with stable hypercapnia in the stable phase did not benefit from the VAPS mode. This meta-analysis of five RCTs including 150 patients with stable hypercapnia COPD compared the efficiency of the VAPS and PS modes, and the results showed that VAPS could improve ventilation and sleep efficacy; however, no significant difference was found between the VAPS and PS groups. Significant differences were found in the patients’ subjective feelings, but the improvement in objective indexes in the VAPS group was not obvious. Two studies measured the health-related quality of life, but the diversity of measurement tools made integration difficult. Furthermore, two studies had different conclusions. Therefore, no data were available for comparison.
Overall completeness and applicability of the evidence Our study subjects were stable hypercapnia COPD patients, and we focused mainly on patients with moderate to severe disease. Our study could not reflect the condition of patients with acute hypercapnia or milder COPDs. One study25 on non-invasive ventilation and sleep indicated that the VAPS mode is suitable for patients with COPD, and compensates for disease progression. However, two studies26,27 showed that the VAPS mode could confer a small benefit to patients with acute hypercapnia, while other studies yielded different conclusions. The duration of NIV with the VAPS mode was more than 1 month in a majority of the included studies, and the crossover trial was used in most of the included studies. Previous articles28 have confirmed that such articles on patients with chronic respiratory
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conditions were insufficient. To improve the tolerance of stable COPD patients for NIV, the VAPS mode is worth recommending. However, one limitation was identified in this meta-analysis: the VAPS mode could only improve patients’ subjective feelings. Quality of the evidence The quality of the included studies in this review was low to moderate. In assessments of the risk of bias, random sequence generation reached 100%, but three studies showed several attrition biases that may have a huge effect on the outcome. More than 50% of the included studies had missing information, so the performance bias level was unclear. This could be attributable to the physical nature of the interventions. Because NIV use could not be blinded, the researchers and patients were aware of the mode of therapy that was chosen; thus, none of the studies were performed with a blind method. Detection bias should be avoided, but only one study described the process of blind measurement in detail. Considering the small number of available articles and the small sample sizes, the evidence level of our study was downgraded to low level according the requirements of the GRADE system. Potential biases in the review process Two review authors independently selected studies and assessed the risk of bias of the included studies, and divergences between the two reviewers were settled by the third reviewer. Both RCTs and crossover RCTs were incorporated to our review. In terms of data extraction, we may take no account of the specificity of crossover RCTcarry-over effect, although the analysis method we used was recommended by the Cochrane handbook29: extraction of A phase and B phase date, followed by A vs. B parallel experiments. However, this approach could make the range of CI too wide even though it addressed the clinical heterogeneity. Research on the ventilation mode of patients with COPD is mostly restricted to the treatment of acute symptoms during hospitalization or in the context of ventilator intolerance, such as studies comparing high-intensity vs. low-intensity ventilation,30 so there is less research on the ventilation status of patients in the stable phase and these two modes, which further led to a smaller sample size in this study. At the same time, statistical analysis of the patient's sleep quality was not easy due to the different evaluation tools used, and the use of meta-integrated descriptions reduced the intuitiveness in the results of the sleep effects of the two non-invasive ventilation modes. Agreements and disagreements with other studies or reviews The findings of the study seemed to confirm that the VAPS mode has similar efficacy as the PS mode. This outcome was consistent with the published studies in patients with chronic respiratory failure.3134 Those studies or literature reviews analyzed participants with various other diseases like asthma, OSA, or kyphoscoliosis, but this meta-analysis reported the effect of the VAPS mode in comparison with the PS mode in stable COPD patients with chronic respiratory failure for the first time. Meanwhile, we considered patients with chronic respiratory failure, who received long-term noninvasive respiratory therapy at home. We not only focused on the effectiveness of mechanical ventilation, but also the quality of sleep and quality of life, which were more important for chronic disease management. Limitations This study was limited by small sample size overall; the result extrapolation has certain limitations. Furthermore, quality of included studies was low to moderate. Therefore, the results of this study
would need to be further demonstrated by some high-quality studies. Finally, the outcome of patients' subjective feelings was less reported and the research tools were inconsistent cause the result based on a minority of the studies, which the patient's subjective feelings were better. Ideally and in future studies, this limitation can be corrected when the researchers were transferred the main outcome indicators to the patients' feelings and adopted more objective research tools. Conclusion Implications for practice This review indicated that the VAPS group was better compared to the PS group with stable COPD in terms of the patients’ subjective feelings, but the improvement in objective indicators in the VAPS group was not obvious. This review suggested when the patients were unable to tolerate the PS mode, the VAPS mode could be used as an alternative to make the patients feel better. The patient's sleep experience, tolerance, and laboratory standards could be comprehensively considered, but also their environmental and economic tolerance, since volume-assured pressure support devices are more expensive than other modes. At the same time, VAPS were performed in the included studies for more than 1 month, and patients could be instructed to adhere to it for a long time during application, with periodical evaluating and monitoring. Implications for research Since only a small number of original randomized controlled studies and the reported outcome used multiple tools, this review only included five articles. Moreover, the sample sizes in the included studies were small. Therefore, it is necessary to experiment with more randomized clinical trials with larger sample sizes to investigate the effect of the VAPS mode on the quality of life, including the levels of anxiety and depression. Second, the sleep and quality of life assessment tools used in the trials included in this study were inconsistent, which reduced the intuitiveness of the results of this study. PSG has good reliability and validity as a tool for sleep, and SGRQ's assessment of the quality of life of patients with COPD is also very comprehensive. Therefore, in the future research we recommended that these two tools be used to evaluate the effect of this modality. Declaration of Competing Interest The authors declare that they have no conflicts of interest related to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Acknowledgement This study was supported by a grant from the National Key R&D Program of China (2018YFC131600); Fudan University for the “Double First-Class Key Discipline Construction, 2018-40-2200 . Appendix 1 PubMed search details 1 # "Pulmonary Disease, Chronic Obstructive"[Mesh] 2 # volume assured pressure support[Title/Abstract] 3 # volume targeted pressure support[Title/Abstract] 4 # volume [All Fields] AND limited [All Fields] AND pressure support [Title/Abstract] 5 # 2 OR 3 OR 4 6 # 1 AND 5 7 # 6 limit clinical trail
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Analysis 1.1. Forest plot for comparison of pH between VAPS and PS.
Analysis 1.2. Forest plot for comparison of PaCO2 between VAPS and PS.
Analysis 1.3. Sensitivity analysis: Forest plot for comparison of PaCO2 between VAPS and PS.
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Analysis 1.4. Forest plot for comparison of PaO2 between VAPS and PS.
Analysis 1.5. Forest plot for comparison of mSaO2 between VAPS and PS.
Analysis 1.6. Forest plot for comparison of on PtcCO2 between VAPS and PS.
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Analysis 1.7. Sensitivity analysis: Forest plot for comparison of PtcCO2 between VAPS and PS.
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18. Coughlin S, Liang WE, Parthasarathy S. Retrospective assessment of home ventilation to reduce rehospitalization in chronic obstructive pulmonary disease. J Clin Sleep Med. 2015;11(6):663–670. 19. Crisafulli E, Manni G, Kidonias M, Trianni L, Clini EM. Subjective sleep quality during average volume assured pressure support (AVAPS) ventilation in patients with hypercapnic COPD: a physiological pilot study. Lung. 2009;187(5):299–305. 20. Oscroft NS, Ali M, Gulati A, et al. A randomised crossover trial comparing volume assured and pressure preset noninvasive ventilation in stable hypercapnic COPD. COPD: J Chron Obstruct Pulmon Dis. 2010;7(6):398–403. 21. Ekkernkamp E, Storre JH, Windisch W, Dreher M. Impact of intelligent volumeassured pressure support on sleep quality in stable hypercapnic chronic obstructive pulmonary disease patients: a randomized, crossover study. Respiration. 2014;88(4):270–276. 22. Oscroft NS, Chadwick R, Davies MG, Quinnell TG, Smith IE. Volume assured versus pressure preset non-invasive ventilation for compensated ventilatory failure in COPD. Respir Med. 2014;108(10):1508–1515. 23. Nilius G, Katamadze N, Domanski U, Schroeder M, Franke KJ. Non-invasive ventilation with intelligent volume-assured pressure support versus pressure-controlled ventilation: effects on the respiratory event rate and sleep quality in COPD with chronic hypercapnia. Int J Chron Obstruct Pulmon Dis. 2017;12:1039–1045. 24. Piesiak P, Brzecka A, Kosacka M, Jankowska R. Efficacy of noninvasive volume targeted ventilation in patients with chronic respiratory failure due to kyphoscoliosis. Adv Exp Med Biol. 2015;838:53–58. 25. Nicolini A, Banfi P, Grecchi B, et al. Non-invasive ventilation in the treatment of sleep-related breathing disorders: a review and update. Rev Port Pneumol. 2014;20 (6):324–335. 26. Briones Claudett KH, Briones Claudett M, Chung Sang Wong M, et al. Noninvasive mechanical ventilation with average volume assured pressure support (AVAPS) in patients with chronic obstructive pulmonary disease and hypercapnic encephalopathy. BMC Pulm Med. 2013;13:12. 27. Hussein K. Non invasive spontaneous dual ventilation in critically ill patients with chronic obstructive pulmonary disease. Egypt J Chest Dis Tuberc. 2016;65(1):99– 104. 28. Ambrogio C, Lowman X, Kuo M, Malo J, Prasad AR, Parthasarathy S. Sleep and noninvasive ventilation in patients with chronic respiratory insufficiency. Intensive Care Med. 2009;35(2):306–313. 29. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 Cochrane. 2011. updated March 2011; training.cochrane.org/handbook/archive/v5.1/. 30. Duiverman ML. Noninvasive ventilation in stable hypercapnic COPD: what is the evidence? ERJ Open Res. 2018;4(2):00012–02018. 31. Murphy PB, Davidson C, Hind MD, et al. Volume targeted versus pressure support non-invasive ventilation in patients with super obesity and chronic respiratory failure: a randomised controlled trial. Thorax. 2012;67(8):727–734. 32. McArdle N, Rea C, King S, et al. Treating chronic hypoventilation with automatic adjustable versus fixed epap intelligent volume-assured positive airway pressure support (iVAPS): a randomized controlled trial. Sleep. 2017;40(10):zsx136. 33. Pluym M, Kabir AW, Gohar A. The use of volume-assured pressure support noninvasive ventilation in acute and chronic respiratory failure: a practical guide and literature review. Hosp Pract. 2015;43(5):299–307. 34. Turk M, Aydogdu M, Gursel G. Effects of modes, obesity, and body position on noninvasive positive pressure ventilation success in the intensive care unit: a randomized controlled study. Turk Thorac J. 2018;19(1):28–35.
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Effects of volume-assured pressure support noninvasive ventilation in stable COPD with chronic respiratory failure: Meta-analysis and literature review Xiaomin Zhangc, Piaoyu Yanga, Chengyao Guoc, Shanqun Lib,**, Yuxia Zhanga,* a
Department of Nursing, Zhongshan Hospital, Fudan University, Shanghai, 200032, China Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China c Nursing School, Fudan University, Shanghai, 200032, China b
A R T I C L E
I N F O
Article History: Received 9 September 2019 Revised 13 January 2020 Accepted 22 January 2020 Available online xxx Keywords: Volume-assured pressure support Noninvasive positive pressure ventilation Chronic obstructive pulmonary disease Sleep Quality of life
A B S T R A C T
Background: Patients receiving long-term home noninvasive ventilation (NIV) may slow down the progression to acute exacerbation of chronic obstructive pulmonary disease (AECOPD), however, the problem with respiratory instability during sleep diminished was persisted, which may reduce the effectiveness of NIV and the patient’s quality of life. A novel NIV mode with volume-assured pressure support (VAPS) has been gradually applied to improve sleep quality in COPD patients with chronic respiratory failure. This meta-analysis aimed to evaluate the efficacy of VAPS in stable COPD patients with chronic respiratory failure. Methods: We performed an electronic literature search for RCTs from January 2008 to October 2018. Studies investigating the effects of VAPS in stable COPD patients with chronic respiratory failure were conducted, and the following primary outcomes were reviewed: effectiveness of ventilation, sleep quality, and quality of life. Results: Five studies with 150 subjects were identified. While questionnaire scores showed significant improvements in the VAPS mode, no significant difference was found in the effectiveness of ventilation (pH, MD = 0.01 [95% CI -0.01 to 0.02, P = 0.27]; PaCO2, MD = 1.25 [95% CI -1.45 to 3.95, P = 0.37]; PaO2, MD = 3.14 [95% CI -0.76 to 7.05, P = 0.11]; mSaO2, MD = 0.23 [95% CI -1.22 to 1.67, P = 0.76]; mPtcCO2, MD = 3.03 [95% CI -6.06 to- 0.60, P = 0.10]). The VAPS mode did not seem to ameliorate sleep quality and quality of life. Conclusion: The VAPS mode had similar efficacy as the pressure-support (PS) mode. However, VAPS could significantly improve the patients’ subjective feelings. © 2020 Elsevier Inc. All rights reserved.
Introduction Chronic obstructive pulmonary disease (COPD) is a leading but underestimated cause of mortality worldwide that is predicted to move from the fourth to third position in terms of morbidity during 19902020, just behind ischemic heart disease and stroke worldwide,1 and from the sixth to third position as the most common cause of death.2 COPD is a common disease characterized by recurrent respiratory symptoms and persistent airflow limitation.1 Along with progressive aggravation, COPD patients show a high risk of relapse. With the increase in the number of smokers in developing countries and the aging population in developed countries, the number of
* Corresponding author: Yuxia Zhang, Department of Nursing, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China, 200032. ** Shanqun Li, Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China, 200032. E-mail addresses: [email protected] (S. Li), [email protected] (Y. Zhang). https://doi.org/10.1016/j.hrtlng.2020.01.007 0147-9563/© 2020 Elsevier Inc. All rights reserved.
COPD patients is increasing.2 COPD results in a decline in the quality of life and increasing social and financial burdens. Moreover, as the disease progresses, patients with moderate to severe COPD are prone to show respiratory failure. The GOLD 2019 report1 noted that patients with persistent daytime hypercapnia could benefit from noninvasive positive pressure ventilation (NIPPV), which has been used worldwide for patients with acute or chronic respiratory failure in recent years.35 Several studies6,7 have suggested that NIPPV is likely to play an important role in intensive care units (ICUs). It could reduce the length of ICU stays and the incidence of pneumonia. In 2017, a meta-analysis8 suggested that NIPPV could improve the partial pressure of arterial oxygen (PaO2) in COPD patients with stable hypercapnia, and found that COPD patients could benefit from the high-pressure mode of NIPPV.9 NIPPV can be divided into two types10: pressure- or volume-control mode. Currently, continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) use the pressure-control (PS) mode.11 Higher pressures can cause respiratory muscle fatigue and
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increase the incidence of dyspnea in COPD patients, so physicians should chose the ventilation mode carefully. Meanwhile, a metaanalysis showed that while NIPPV could improve PaCO2 over the short term, it did not show any significant long-term effectiveness in alleviating dyspnea and promoting daily activity levels.12 Therefore, identification of an appropriate ventilation mode is crucial. BiPAP provides two levels of pressure: an inspiratory positive airway pressure (IPAP) and a lower expiratory positive airway pressure (EPAP), which increase the patient's inspiratory depth and the quantity of inhaled air and improve auxiliary ventilation. However, the disadvantage is that once the air leaks, it will greatly interfere with the patient-machine synchronization. CPAP machines were initially used mainly by patients for treatment of sleep apnea at home, but they are now widely used in intensive care units. The pressure in the CPAP mode is too high for patients to tolerate for long periods of time. However, many studies have also shown that the pressure- or volume-control modes have their unique advantages.13,14 For instance, the pressure-control mode can be adjusted according to the peak inspiration pressure of the patient, thus increasing patient comfort15; similarly, the volume-control mode can guarantee an effective tidal volume in the minimum ventilation time.16 These unique advantages indicate the need for a mixed volume and pressure mode. Combining the advantages of these two modes, volume-assured pressure support (VAPS), a hybrid mode, measures the target volume based on the patient's characteristics, such as the degree of airway restriction, patient coordination, and the ability to automatically regulate peak inspiration and expiratory pressure.17 Several recent RCTs have compared the effectiveness of VAPS with BiPAP in stable COPD patients with respiratory failure and shown that the ventilation outcomes were better in the VAPS group. Coughlin et al.18 indicated that VAPS could decrease readmissions and relieve the resultant financial burden. However, since these studies had some limitations, including short intervention times and small sample sizes, the application of VAPS is worth further investigation. Therefore, we have evaluated the impact of the VAPS mode in stable COPD patients with respiratory failure, including assessment of efficacy of ventilation, sleep quality, and quality of life. Methods Search strategy We conducted a comprehensive assessment by searching the Cochrane Library, CINAHL, EMBASE, PubMed, and Web of Science for RCTs with human participants from the establishment of the database to September 2018; meeting abstracts and "gray" literature were excluded from the search. The following medical subject heading (MeSH) terms were used as key words: “Pulmonary Disease, Chronic Obstructive,” “volume assured pressure support,” “volume targeted pressure support,” and “volume limited pressure support.” The literature search was conducted independently by two reviewers (ZHANG and YANG). The search strategy for PubMed is shown in Appendix 1. Inclusion and exclusion criteria The included studies met the following criteria: (1) patients with COPD GOLD stage III or IV (forced expiratory volume in 1 second (FEV1)/forced vital capacity < 70% and FEV1 < 50% predicted); (2) patient age between 40 and 76 years with stable clinical condition (no exacerbation in the four weeks prior to study participation together with a pH > 7.35); (3) a history of chronic hypercapnic respiratory failure (an arterial carbon dioxide pressure (PaCO2) > 6.0 kPa at rest while breathing room air); (4) VAPS mode used in the intervention group, and volume- or pressure control used
in the control group; and (5) an RCT design and publication in English. Studies were screened independently by the two reviewers. Data extraction and quality assessment An approach based on the Cochrane Risk of Bias 2014 RCT evaluation tool was used. A risk of bias assessment of the included studies was separately performed by two reviewers (ZHANG and GUO). Divergences between the two reviewers in specific studies were settled by the third reviewer (YANG). The data were extracted by the reviewer ZHANG, and the following study characteristics were collected: study ID, patient characteristics, sample size, study design (intervention and control measures), and outcome. The results of data extraction were verified by the reviewer YANG. Statistical analysis The mean difference (MD) was selected while estimating the total effect of continuous variables. Next, the standardized mean difference (SMD) was selected while combining outcomes measured on different scales by listing them based on their standard deviations. Heterogeneity was tested and significance was set at P < 0.05. We used the fixed model if there was low heterogeneity, and the metaanalyses findings that could not be evaluated due to significant heterogeneity were reported narratively. We used Review Manager 5.3 to pool the results and assess the treatment efficacy. Both the pooled effects and 95% confidence intervals (CIs) were calculated. Forest plots were used to display the results visually, and funnel plots were used to describe publication bias. Results Search results The process of study selection is shown in Fig. 1. A total of 241 studies were retrieved through the database searches. Among these, five eligible studies1923 with 150 subjects were included in this meta-analysis: one was an RCT and the remaining four were randomized crossover studies. Characteristics of the included studies The “characteristics of the included studies” table presents detailed descriptions of the methods, participants, interventions, and outcomes (Table 1). Characteristics of excluded studies The reasons for excluding studies were provided by the reviewers, and they included incompatible study type (n = 89), use of non-volume- and pressure-control mode (n = 33), and a disease type that did not meet the inclusion criteria (n = 35). After assessment of the full text of the articles, eight were excluded, with four articles assessing a mixture of COPD patients and those showing asthma, obstructive sleep apnea (OSA), or kyphoscoliosis; two articles assessing a mixed VAPS mode with PS mode in the intervention; and two studies for which the full text could not be obtained limited for language. Risk of bias in the included studies A graphical overview of our assessments for the six standards, namely, selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias, is provided in Fig. 2. All studies had clearly described the randomization process. Three studies used appropriate allocation and concealment methods and
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Fig. 1. Study flow diagram. Search performed in October 2018.
two reported that the participants were blinded for the interventions. However, only one study reported blinding of the outcome assessment: three studies had a high risk of incomplete outcome, and most studies had a low risk of reporting bias and other bias.
in favor of the experimental group, which was not significant (95% CI 1.38 to 6.00, Analysis 1.3). Thus, the result shows stabilization.
Effects of the intervention
Four of the five trials assessed this outcome in a total of 55 participants in the experimental group and 55 in the control group. The common effect (mean difference) in power was 3.14 in favor of the control group, which was not significant (95% CI 0.76 to 7.05, Analysis 1.4).
Efficacy of ventilation Arterial blood gas (ABG) was most widely used index to show the efficacy of ventilation, which also included assessments of post-procedure pH, PaCO2, PaO2, etc. Meanwhile, minute ventilation (VE) was also used frequently. pH Three of the five trials included this outcome: a total of 35 s participants in the experimental group and 35 in the control group. The common effect (mean difference) in power was 0.01 in favor of the control group (95% CI 0.01 to 0.02, Analysis 1.1). PaCO2 Four studies measured the PaCO2 in a total of 55 participants in the experimental group and 55 in the control group. The common effect (mean difference) in power was 1.25 in favor of the experimental group (95% CI 1.45 to 3.95, Analysis 1.2). However, the forest plot shows that one study24 had a high weight. Therefore, we removed that study from sensitivity analysis. As a result, the power was 2.31
PaO2
mSaO2 Three trials assessed this outcome in a total of 52 participants in the experimental group and 52 in the control group. The common effect (mean difference) in power was 0.23 in favor of the control group, which was not significant (95% CI 1.22 to 1.67, Analysis 1.5). mPtcCO2 Four trials assessed this outcome in a total of 66 participants in the experimental group and 66 in the control group. The common effect (mean difference) in power was 3.39 in favor of the control group (95% CI 6.05 to- 0.73, Analysis 1.6). However, we found that the study26 had a high weight, so we removed that study from sensitivity analysis. As a result, power was 3.03 in favor of the control group, which did not show statistical significance (P = 0.10, Analysis 1.7).
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X. Zhang et al. / Heart & Lung 00 (2020) 19 Table 1 Characteristics of the included studies. Sample
Design
I
C
Intervention
Control
Outcomes
Ernesto Crisafulli 2009
Stable COPD 9
9
- IPAP was set at the patient’s maximal tolerated level (up to 30 cmH2O). 5-day periods
①②③⑨⑪⑫
Nichholas S. Oscroft 2010
Stable COPD 12
12
Stable COPD 20
20
Emelie Ekkernkamp 2014
Stable COPD 14
14
-The inspiratory trigger was left in the default setting and cycling to expiration was at 25% of the maximal inspiratory flow. 8 weeks - The expiratory pressure was set at 5 cmH20 and the inspiratory pressures were increased and inspiratory time and backup rate adjusted to optimize ventilation with the aim of reducing PtcCO2 3 months -Established on effective ventilation
①②③④⑤⑥⑦⑧⑩
Nichholas S. Oscroft 2014
-Target tidal volume was set to 8 ml/kg of the patient’s ideal body weight -IPAP ranging from EPAP up to 30 cmH2O - 5-day period -Yielded an average figure of minute ventilation that was adopted as the TgV - Adjustment of inspiratory pressure up to 25 cm H2O 8 weeks - Recorded the minute ventilation and respiratory rate -Attempted to reproduce TgV overnight automatically by adjusting the inspiratory pressures in the range of 725 cmH2O. 3 months - Established on effective ventilation, combined pressure-support ventilation with TgV -Quickly adjusted when the ventilation was below the target ventilation 6 weeks -iVAPS: adjusted to reduce pCO2 to 50 mmHg, measured by capillary blood samples in the morning about 1 h after the end of nocturnal ventilation -Inspiratory pressure was increased gradually. 1 night
Study
Patients
Gerog Nilius 2017
Stable COPD 20
20
②③④⑤⑥⑦⑧
①②③⑤⑩⑫
-Ventilators and ventilator settings were not changed 6 weeks -ST: adjusted to reduce pCO2 to 50 mmHg, ④⑤⑪⑫ measured by capillary blood samples in the morning about 1 h after the end of nocturnal ventilation -Inspiratory pressure was increased gradually. 1night
①pH②PaCO2③PaO2④mSaO2⑤ mPtcCO2⑥ SWT⑦ SF-36⑧ SGRQ⑨VE⑩VAS⑪ Sleep questionnaire ⑫ PSG Abbreviations: IPAP: inspiratory positive airway pressure; EPAP: expiratory positive airway pressure, TgV: target minute ventilation, PaO2: partial pressure of arterial oxygen; PaCO2: partial pressure of arterial carbon dioxide, VAS: visual analog scale, SGRQ: St George’s Respiratory Questionnaire, SWT: shuttle walk test, VE: minute ventilation, mPtcCO2: Mean nocturnal PtcCO2, mSaO2: Mean nocturnal SaO2, PSG: polysomnography, SF-36: short form 36, PIP: Peak inspiratory pressure.
Minute ventilation Minute ventilation was measured in one of the five trials. In this trial, where 9 participants in the VAPS group were compared to 9 participants in the control group, the result showed that differences in minute ventilation between groups did not have statistical significance. Effects on sleep Polysomnography PSG as a sensitive indicator of sleep monitoring was performed in two clinical trials. PSG records the total sleep time, sleep efficiency, N1 sleep, N2 sleep, N3/4 sleep, REM sleep, etc. In one trial,21 14 participants in the iVAPS group were compared to 14 participants in the control group with no significant difference. In other trials, where 20 participants in the iVAPS group were compared to 20 participants in the control group, apart from sleep efficiency (TST/time in bed), which was slightly higher in the iVAPS group than in the pressurecontrolled mode group (p = 0.056), no other parameter showed significance.23
sleep, morning freshness, pressure-included discomfort, and mask fit and found that the differences in the comfort level were significant, and the patients in iVAPS group were more comfortable. Sleep questionnaire Two studies19,23 used sleep questionnaires to measure sleep quality. One trial used a ten-item questionnaire (score 010, with 10 corresponding to the worst sleep quality) and found that the AVAPS group showed more efficient sleep. Another trial used a five-item questionnaire (score 05, where a lower score indicated better acceptability), and the results showed no significant statistical differences between the two ventilation modes (p = 0.142). Health-related quality of life Two studies20,22 investigated the effect of VAPS on the HRQL by evaluating the SF-36, St George’s Respiratory Questionnaire (SGRQ), and shuttle walk test (SWT). The follow-up time of one trial20 was 8 weeks, and the difference did not show significance. The follow-up time of the other trial20 was three months, and there were significant improvements in total SGRQ and SF-36 emotional summary scores in the VAPS group.
Visual analogue scale Discussion The visual analogue scale (VAS) is used to assess the sleep quality associated with the ventilators. Three trials measured VAS. One trial19 only showed that the comfort level significantly improved with ventilation. Another clinical trial20 showed improvements in usage, tolerability, comfort level, and sleep quality, but no significant difference in VAS scores. The third study recorded the restfulness of
Summary of the main results VAPS, including AVAPS and iVAPS, is a hybrid-ventilation mode, but its principle is still based on pressure support. There are compelling data showing that VAPS had significant therapeutic effects
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Fig. 2. Database search (n = 241)PubMed = (6), EMBASE = (38), MEDLINE = (14), CINAHL = (6), Cochrane Library = (125),Web of Science = (52)173 records after removing duplicates (241 - 68 = 173)13 records after reading title/abstracts160 records excludedP (patients):35I (intervention):33O (outcome):3S (study): 895 records after reading the full text8 texts excludedP: 4 included other diseases, such as OSAI: 2 used VAPS+PSLanguage: 2 Database search (n = 241)PubMed = (6), EMBASE = (38), MEDLINE = (14), CINAHL = (6), Cochrane Library = (125),Web of Science = (52)173 records after removing duplicates (241 - 68 = 173)13 records after reading title/abstracts160 records excludedP (patients):35I (intervention):33O (outcome):3S (study): 895 records after reading the full text8 texts excludedP: 4 included other diseases, such as OSAI: 2 used VAPS+PSLanguage: 2 Fig. “Risk of bias” summary: review of authors’ judgements for each risk of bias item in each included study.
against hypoventilation with or without obesity in patients with chronic or acute hypercapnia respiratory failure caused by OSA and kyphoscoliosis,24 but our study found that patients with stable hypercapnia in the stable phase did not benefit from the VAPS mode. This meta-analysis of five RCTs including 150 patients with stable hypercapnia COPD compared the efficiency of the VAPS and PS modes, and the results showed that VAPS could improve ventilation and sleep efficacy; however, no significant difference was found between the VAPS and PS groups. Significant differences were found in the patients’ subjective feelings, but the improvement in objective indexes in the VAPS group was not obvious. Two studies measured the health-related quality of life, but the diversity of measurement tools made integration difficult. Furthermore, two studies had different conclusions. Therefore, no data were available for comparison.
Overall completeness and applicability of the evidence Our study subjects were stable hypercapnia COPD patients, and we focused mainly on patients with moderate to severe disease. Our study could not reflect the condition of patients with acute hypercapnia or milder COPDs. One study25 on non-invasive ventilation and sleep indicated that the VAPS mode is suitable for patients with COPD, and compensates for disease progression. However, two studies26,27 showed that the VAPS mode could confer a small benefit to patients with acute hypercapnia, while other studies yielded different conclusions. The duration of NIV with the VAPS mode was more than 1 month in a majority of the included studies, and the crossover trial was used in most of the included studies. Previous articles28 have confirmed that such articles on patients with chronic respiratory
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conditions were insufficient. To improve the tolerance of stable COPD patients for NIV, the VAPS mode is worth recommending. However, one limitation was identified in this meta-analysis: the VAPS mode could only improve patients’ subjective feelings. Quality of the evidence The quality of the included studies in this review was low to moderate. In assessments of the risk of bias, random sequence generation reached 100%, but three studies showed several attrition biases that may have a huge effect on the outcome. More than 50% of the included studies had missing information, so the performance bias level was unclear. This could be attributable to the physical nature of the interventions. Because NIV use could not be blinded, the researchers and patients were aware of the mode of therapy that was chosen; thus, none of the studies were performed with a blind method. Detection bias should be avoided, but only one study described the process of blind measurement in detail. Considering the small number of available articles and the small sample sizes, the evidence level of our study was downgraded to low level according the requirements of the GRADE system. Potential biases in the review process Two review authors independently selected studies and assessed the risk of bias of the included studies, and divergences between the two reviewers were settled by the third reviewer. Both RCTs and crossover RCTs were incorporated to our review. In terms of data extraction, we may take no account of the specificity of crossover RCTcarry-over effect, although the analysis method we used was recommended by the Cochrane handbook29: extraction of A phase and B phase date, followed by A vs. B parallel experiments. However, this approach could make the range of CI too wide even though it addressed the clinical heterogeneity. Research on the ventilation mode of patients with COPD is mostly restricted to the treatment of acute symptoms during hospitalization or in the context of ventilator intolerance, such as studies comparing high-intensity vs. low-intensity ventilation,30 so there is less research on the ventilation status of patients in the stable phase and these two modes, which further led to a smaller sample size in this study. At the same time, statistical analysis of the patient's sleep quality was not easy due to the different evaluation tools used, and the use of meta-integrated descriptions reduced the intuitiveness in the results of the sleep effects of the two non-invasive ventilation modes. Agreements and disagreements with other studies or reviews The findings of the study seemed to confirm that the VAPS mode has similar efficacy as the PS mode. This outcome was consistent with the published studies in patients with chronic respiratory failure.3134 Those studies or literature reviews analyzed participants with various other diseases like asthma, OSA, or kyphoscoliosis, but this meta-analysis reported the effect of the VAPS mode in comparison with the PS mode in stable COPD patients with chronic respiratory failure for the first time. Meanwhile, we considered patients with chronic respiratory failure, who received long-term noninvasive respiratory therapy at home. We not only focused on the effectiveness of mechanical ventilation, but also the quality of sleep and quality of life, which were more important for chronic disease management. Limitations This study was limited by small sample size overall; the result extrapolation has certain limitations. Furthermore, quality of included studies was low to moderate. Therefore, the results of this study
would need to be further demonstrated by some high-quality studies. Finally, the outcome of patients' subjective feelings was less reported and the research tools were inconsistent cause the result based on a minority of the studies, which the patient's subjective feelings were better. Ideally and in future studies, this limitation can be corrected when the researchers were transferred the main outcome indicators to the patients' feelings and adopted more objective research tools. Conclusion Implications for practice This review indicated that the VAPS group was better compared to the PS group with stable COPD in terms of the patients’ subjective feelings, but the improvement in objective indicators in the VAPS group was not obvious. This review suggested when the patients were unable to tolerate the PS mode, the VAPS mode could be used as an alternative to make the patients feel better. The patient's sleep experience, tolerance, and laboratory standards could be comprehensively considered, but also their environmental and economic tolerance, since volume-assured pressure support devices are more expensive than other modes. At the same time, VAPS were performed in the included studies for more than 1 month, and patients could be instructed to adhere to it for a long time during application, with periodical evaluating and monitoring. Implications for research Since only a small number of original randomized controlled studies and the reported outcome used multiple tools, this review only included five articles. Moreover, the sample sizes in the included studies were small. Therefore, it is necessary to experiment with more randomized clinical trials with larger sample sizes to investigate the effect of the VAPS mode on the quality of life, including the levels of anxiety and depression. Second, the sleep and quality of life assessment tools used in the trials included in this study were inconsistent, which reduced the intuitiveness of the results of this study. PSG has good reliability and validity as a tool for sleep, and SGRQ's assessment of the quality of life of patients with COPD is also very comprehensive. Therefore, in the future research we recommended that these two tools be used to evaluate the effect of this modality. Declaration of Competing Interest The authors declare that they have no conflicts of interest related to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Acknowledgement This study was supported by a grant from the National Key R&D Program of China (2018YFC131600); Fudan University for the “Double First-Class Key Discipline Construction, 2018-40-2200 . Appendix 1 PubMed search details 1 # "Pulmonary Disease, Chronic Obstructive"[Mesh] 2 # volume assured pressure support[Title/Abstract] 3 # volume targeted pressure support[Title/Abstract] 4 # volume [All Fields] AND limited [All Fields] AND pressure support [Title/Abstract] 5 # 2 OR 3 OR 4 6 # 1 AND 5 7 # 6 limit clinical trail
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Analysis 1.1. Forest plot for comparison of pH between VAPS and PS.
Analysis 1.2. Forest plot for comparison of PaCO2 between VAPS and PS.
Analysis 1.3. Sensitivity analysis: Forest plot for comparison of PaCO2 between VAPS and PS.
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Analysis 1.4. Forest plot for comparison of PaO2 between VAPS and PS.
Analysis 1.5. Forest plot for comparison of mSaO2 between VAPS and PS.
Analysis 1.6. Forest plot for comparison of on PtcCO2 between VAPS and PS.
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Analysis 1.7. Sensitivity analysis: Forest plot for comparison of PtcCO2 between VAPS and PS.
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