Advanced chronic obstructive pulmonary disease (COPD) might result in chronic hypercapnic ventilatory failure. Similar to neuromuscular and restrictive chest wall diseases, long-term non-invasive positive pressure ventilation (NPPV) is increasingly used in chronic hypercapnic COPD. This review describes the methods, patient selection, ventilatory strategies, and therapeutic effects of long-term Home-NPPV based on randomized controlled clinical trials published since 1985 in English language retrieved from the databases PubMed and Scopus. Long-term NPPV is feasible and effective in stable, non-exacerbated COPD patients with daytime hypercapnia with arterial pressure of carbon dioxide (PaCO2) levels ≥50 mm Hg (6.6 kPa), if the applied ventilatory pressures and application times improve baseline hypercapnia by at least 20%. Patients who survived an acute hypercapnic exacerbation might benefit from long-term NPPV if hypercapnia persists 2–4 weeks after resolution of the exacerbation. Pressure-controlled ventilation or pressure-support ventilation with adequate minimum backup breathing frequencies, in combination with nasal masks or oronasal masks have been successfully used in all larger clinical trials. Ventilatory strategies with mean inspiratory pressures of up to 28 cm H2O are well-tolerated by patients, but limitations exist in patients with impaired cardiac performance. Home-NPPV with a PaCO2-reductive approach might be considered as an additional treatment option in patients with stable chronic hypercapnic COPD.

© 2022 S. Karger AG, Basel

Introduction – Why?Pathophysiologic Background of Chronic Ventilatory Failure

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases in Western countries. The disease progresses variably and can result in respiratory failure. Type I respiratory failure with severe hypoxaemia can be qualifying for Long-term oxygen treatment (LTOT). Therapeutic effects of LTOT are improved dyspnoea, exercise tolerance, and health-related quality of life (HRQL) [1]. LTOT is one of the rare COPD treatment options for which improved long-term survival had been reported [2]. In contrast, type II respiratory failure (hypercapnia with or without hypoxaemia) is an indicator of insufficiency of the “ventilatory pump” with subsequent alveolar hypoventilation.

Ventilatory pump failure develops from increased load of inspiratory muscles and/or reduced inspiratory muscle capacity. Acute ventilatory failure is characterized by hypercapnia and respiratory acidosis. In chronic ventilatory insufficiency, hypercapnia may persist, but renal compensatory mechanisms can ameliorate respiratory acidosis over time by bicarbonate retention. In this situation, pH measurements may be normal, and the concentration of blood and tissue HCO3− is elevated [3]. Persistent chronic hypoventilation with elevated arterial pressure of carbon dioxide (PaCO2) might be understood as a protective mechanism of the central respiratory centres to avoid complete and abrupt breakdown of the respiratory muscle functions. The term “permissive hypercapnia” has been introduced for this situation [4, 5]. Long-term hypercapnia seems to be per se an independent negative prognostic factor [6], and therefore treatment options in advanced respiratory diseases should also target chronic hypoventilation.

In patients with advanced COPD, the reasons for increased load of the inspiratory muscles contain peripheral bronchial obstruction, bronchial mucus impaction, and dynamic hyperinflation of the lungs with increased intrinsic PEEP. Muscle capacity is impaired by hyperinflation-induced diaphragm flattening, in combination with ineffective muscle function due to impaired muscle fibre structure, biochemistry, and contractile function [7].

There are no characteristic symptoms in patients with chronic hypercapnic respiratory failure. Apart from the symptoms of COPD and comorbidities, patients might develop sleep-disordered breathing with daytime sleepiness, morning headache, and peripheral oedema [8].

Similar to restrictive thoracic and neuromuscular disorders, long-term or home mechanical non-invasive positive pressure ventilation (Home-NPPV) has been increasingly used in COPD patients in the last years. The target populations are patients with advanced disease and chronic alveolar hypoventilation [9]. Home-NPPV has received considerable scientific attention, as demonstrated by the number of recent studies related to COPD patients and long-term NPPV following acute hypercapnic respiratory failure [10, 11] or chronic stable hypercapnic respiratory failure [12-14].

Mechanical Ventilation

Chronic ventilatory pump failure with subsequent alveolar hypoventilation is the most important reason to start long-term ventilator treatment. The best indicator for chronic ventilatory failure is an elevated PaCO2, while pH is normal. According to conditional recommendations published by the German National Guideline for Treating Chronic Respiratory Failure, criteria for initiation of Home-NPPV are daytime PaCO2 levels of 50 mm Hg (6.6 kPa) or above, nocturnal PaCO2 of 55 mm Hg (7.3 kPa) or above, or mild daytime hypercapnia (PaCO2 45–50 mm Hg; 5.9–6.6 kPa) with nocturnal rise of PaCO2 by at least 10 mm Hg (1.3 kPa) [15].

The physiologic targets of non-invasive mechanical ventilation are unloading of the ventilatory pump, resting and regeneration of ventilatory muscles, resetting of CO2 sensitivity in the central breathing centres, and improvements in pulmonary mechanics [16-18]. The most important physiologic outcome parameter in patients with chronic hypercapnic respiratory failure is reduction of the elevated PaCO2 level. In stable COPD patients with long-term NPPV, blood gases can be improved not only during NPPV application but also during periods of subsequent spontaneous breathing [19].

Who?Patient Selection and Effects of Long-Term NPPV

Home-NPPV is an established treatment option in patients with restrictive thoracic disorders and in patients with neuromuscular diseases with hypercapnic respiratory failure [15]. In chronic stable hypercapnic COPD, the indication for Home-NPPV has been a controversially discussed issue. Early long-term studies from the late 1990s until 2009 studied NPPV in small cohorts of COPD patients with moderate chronic hypercapnia. Casanova et al. [20] and Clini et al. [21] concluded that stable COPD patients did not gain survival benefits when long-term NPPV was added to standard COPD care. McEvoy et al. [22] found in a cohort of 144 patients a small positive survival effect by additional Home-NPPV after 2 years, for the price of slightly worsened HRQL. In this early phase of clinical trials, “doses” of NPPV (pressure support and ventilation periods) were relatively low. Mean inspiratory pressure (IPAP) support ranged from 12 to 14 cm H2O, and many patients used NPPV for less than 5 h per day. A further important aspect was patient selection: all three studies investigated the effects of Home-NPPV in a subgroup of COPD patients with a mean PaCO2 below 55 mm Hg (7.3 kPa).

Consequently, more recent clinical trials focused on patients with more severe hypercapnia and applied higher pressure support and longer treatment periods per day. This innovative approach was realized in two smaller studies with mean IPAP levels of 28 cm H2O in combination with either a pressure-controlled ventilation mode or a pressure-support mode, both with high backup rates between 17.5 and 21 breath/min, respectively [23, 24]. Each of these studies showed a significant improvement in outcomes following initiation of Home-NPPV. A similar treatment approach was applied in the German/Austrian multicentre randomized controlled trial, published by Köhnlein et al. [12]. This study included 195 stable (at least 4 weeks non-exacerbated) COPD patients. Mean baseline PaCO2 levels were 59 mm Hg (7.8 kPa) in the NPPV group and 58 mm Hg (7.7 kPa) in the control group. The treatment goal in the NPPV group was a reduction of daytime hypercapnia by at least 20% from baseline, or into the normal PaCO2 range. Minimum NPPV application was 6 h per day. 102 patients were randomized into the NPPV group, of whom 91 completed the 1-year follow-up. The results showed a substantial survival benefit for chronic hypercapnic COPD patients using Home-NPPV in comparison to those undergoing standard therapy, including LTOT alone. Secondary endpoints suggest improved 6-min walking distance, lower exacerbation rates, and better HRQL.

Home-NPPV was found to be additionally beneficial when applied in combination with a multidisciplinary rehabilitation programme for COPD patients with (moderate) chronic hypercapnic respiratory failure. Duivermann and co-workers [25, 26] demonstrated improvements in exercise tolerance, HRQL, and lung function, in comparison to rehabilitation alone.

A major problem in the management of advanced COPD is frequent exacerbations with acute hypercapnic respiratory failure and the need for immediate mechanical ventilation (for details about the application of acute NPPV see [27]). COPD patients who survived an exacerbation with acute hypercapnic respiratory failure and NPPV therapy are at increased risk for subsequent severe exacerbations in the near future. Chu et al. [28] reported a readmission rate in the first year after an index exacerbation of 79.9%, and a total mortality of 49.1%. Two large prospective studies investigated the continuation of NPPV at home after a severe exacerbation with regard to survival rates and other outcomes. In a multicentre Dutch study [10], COPD patients with persistent hypercapnia 48 h after termination of acute NPPV were randomized to either standard medical treatment or standard medical treatment and long-term Home-NPPV. After 1 year, no improvements in the time until readmission or death were found in either group, despite a small improvement in HRQL in the NPPV group. Interestingly, not only in the NPPV group but also in the control group, many patients with elevated PaCO2 normalized their hypercapnia in the first 3 months after the index exacerbation.

The second clinical trial [11] recruited patients who experienced an acute hypercapnic exacerbation with the need for acute NPPV, with persistent PaCO2 levels of >53 mm Hg (7.1 kPa) 2 to 4 weeks after the index exacerbation. The primary combined endpoint was time to emergency room readmission or death. Patients were randomized to receive either standard medical treatment that included LTOT (n = 59) or standard medical treatment that included LTOT in combination with Home-NPPV (n = 57). The mean baseline PaCO2 level was 59 mm Hg (7.9 kPa) in both groups. After 1 year, patients who received Home-NPPV experienced a significantly longer time period until their next readmission or death (Home-NPPV + LTOT: 4.3 months vs. LTOT: 1.4 months).

The abovementioned clinical trials provide the current clinical knowledge on Home-NPPV. Their results were the cornerstones of the German National Guideline for Treating Chronic Respiratory Failure in patients with advanced COPD [15]. Key recommendations for patient assessment and decision making in different clinical situations are displayed in Figure 1.

Fig. 1.

Algorithm for assessment of advanced COPD patients for the treatment option non-invasive ventilation (NIV). Adapted from [15], with permission.

How?Technical Aspects and Ventilation StrategyInterfaces

In the last years, a huge number of new ventilator-patient interfaces entered the market. The most important interfaces are nasal masks, oronasal masks, total face masks, or mouth pieces (see Fig. 2) [29]. The selection of interfaces depends on the technique of the ventilator, the ventilation strategy, the patient’s preference, the physiognomy of the patient, and the experience of the therapeutic team [30]. In the majority of the above presented larger long-term clinical trials, mask selection was based on the patients’ comfort. There seems to be a trend towards more frequent use of masks that cover the nose and mouth, as compared to the results of the Eurovent survey [31] published 17 years ago. In that early time of home-ventilation, the most frequently applied type of interface was the nasal mask. A recent survey from 2016 on the patterns of ventilation in Europe confirmed the preference for oronasal or full-face masks [9]. This development is likely attributable to a switch in ventilator settings. With the presentation of high-intensity NPPV by Windisch et al. [23], the average IPAPs in larger Home-NPPV trials increased from 12 cm H2O (Casanova et al. [20]), 14 cm H2O (Clini et al. [21]), and 12.9 cm H2O (McEvoy et al. [22]) to IPAP levels of 21.6 cm H2O (Köhnlein et al. [12]) and 24 cm H2O (Murphy et al. [11]). With the application of higher pressures and longer ventilation times, many prescribers might have abandoned the presumably less well-fitting and more leaking nasal masks, in favour of oronasal or full-face masks [9]. Moreover, it was shown that IPAPs of 25 cm H2O and above improved compliance, and a more significant reduction in PaCO2 could be achieved when oronasal masks were used [29]. A recent review by Lebret et al. [32] concluded that oronasal masks are the most used interface for the delivery of Home-NPPV in patients with COPD, but there was no difference in the efficacy or tolerance between oronasal or nasal masks.

Fig. 2.

Non-invasive mechanical ventilation masks. Top row: full-face mask; middle row: standard oronasal mask, compact oronasal mask, full-face mask with special air tubing; bottom row: nasal pillows, standard nasal mask, mouth piece.

Ventilators and Ventilatory Modes

Apart from adequate mask selection, the choice of the ventilator, ventilator settings, and air humidification plays an important role in successful NPPV treatment. Ventilators designed for Home-NPPV are characterized by high trigger sensitivity and sufficient amounts of air leak compensation. Home-NPPV is nearly always performed in an assisted mode with pressure preset ventilation. The patient paces the ventilation by triggering the ventilator to cycle between two pressure levels. The resulting tidal volume varies with each breath. A minimum respiratory rate can be determined. As long as the spontaneous breathing frequency of the patient is higher than the preset minimum frequency, the patient is ventilated in an assisted mode. During assisted ventilation, sensitive trigger can minimize the reaction time of the ventilator (<30 ms), thereby minimizing the patient’s work of breathing [33, 34]. If the patient’s breathing frequency drops below the minimum rate, the patient is ventilated in a controlled mode with the minimum frequency and the preset pressure levels.

NPPV can also be performed with preset minimum tidal volumes. The disadvantage of volume-targeted ventilation is the high probability of air leaks in the system. Mask ventilation is always associated with intended and unintended air leaks in the region of the interface. With volume-targeted ventilation, the ventilator increases pressures to maintain the preselected tidal volumes, and thereby unintended air leaking might be further increased and application of air volumes to the patient reduced [35].

Recently, new ventilatory modes which combine volume- and pressure-targeted non-invasive ventilation have been introduced by manufacturers. There is a physiological rationale in continuously adapting ventilator parameters to fluctuating patient needs during treatment. In longer terms, respiratory mechanics may change during the course of the disease. During a single treatment session, upper airway patency may vary with body position and sleep stage. Adaptive or auto-titrating pressure modes were designed to deliver optimized IPAPs support to achieve adequate alveolar ventilation and optimized expiratory pressure to stabilize the hypopharynx and the lower airways [36]. In the absence of sufficient scientific evidence for newer ventilatory modes, the Task Force for NPPV of the European Respiratory Society suggests using fixed pressure-support mode as first-choice ventilator mode in patients with COPD [37].

As described above, clinical studies with favourable patient outcomes applied IPAP levels of 22–24 cm H2O and the ventilatory modes pressure-controlled ventilation or pressure-support ventilation with higher backup rates. The conclusions from these observations are the obvious need for a substantial improvement of alveolar ventilation, which might be an important aspect for treatment success and a better outcome in chronic hypercapnic COPD patients [38]. Murphy et al. [39] could demonstrate that sufficiently high pressure levels are decisive, while high breathing frequencies seem to play a secondary role. However, improvement of PaCO2, a direct marker of impaired alveolar ventilation, is the key physiologic target of Home-NPPV.

Similarly important for success and effectiveness of NPPV treatment is compliance. Little is known about long-term acceptance and adherence to NPPV treatment and its impact on the course of severe COPD, despite this might be a major problem in daily practice. In a cross-sectional multicentre study on domiciliary non-invasive ventilation in stable hypercapnic COPD patients, Yazar et al. [40] considered NPPV application periods of at least 5 h per day. The meta-analysis from Struik et al. [41] identified that higher IPAP levels, better compliance, and higher baseline PaCO2 are success parameters to obtain beneficial effects of Home-NPPV therapy.

Since many years, it had been discussed that positive pressure ventilation might impact cardiac output. This aspect becomes clinically important with high-intensity NPPV and longer periods of Home-NPPV. In 2010, Lukácsovits et al. [42] reported that besides the positive effects of high-intensity NPPV, it will also markedly reduce cardiac output. On the other hand, the improvements in gas exchange by high-intensity NPPV might improve oxygenation of all critical organs. To clarify this point, Duiverman et al. [43] published a randomized controlled feasibility study in stable hypercapnic COPD patients. The study compared the effects of high- versus low-intensity Home-NPPV on cardiac output after a home treatment period of 6 weeks. In 14 patients undergoing a cross-over design, no overall adverse effects on cardiac performance (cardiac output and N-terminal proBNP) were detected. In patients with pre-existing heart failure, the application of very high IPAPs might reduce cardiac output. Bearing this aspect in mind, the authors suggest a treatment attempt even in patients with chronic hypercapnic COPD and heart failure.

Health Care Setting for Initiation and Follow-Up of Home-NPPV

Only a few years ago, the initiation and control of Home-NPPV was performed as an inpatient treatment in most European countries. Nowadays there is a trend towards increasing cross-sectoral care with a strengthening of outpatient care [44]. A recently published randomised controlled trial in the Netherlands has pioneered the scientific evaluation of health care settings for COPD patients, demonstrating that outpatient initiation of Home-NPPV leads to a significant reduction in costs, without reducing the effectiveness of the ventilator therapy [45]. Of note, telemonitoring systems are already increasingly used in the Netherlands for outpatient monitoring of Home-NPPV. The implementation of telemedicine monitoring techniques could show significant advantages with regard to Home-NPPV, especially due to the possibility of extracting internal ventilator data.

Outpatient structures without telemedicine or telemonitoring are also gaining popularity across Europe. In a retrospective study from Germany, a special algorithm for an outpatient clinic for follow-up of NPPV based on the Dutch care structure was developed and analysed [46]. Outpatient initiation and control of Home-NPPV in COPD patients seems to be promising. It might reduce treatment delays and avoid unnecessary hospital admission. An ongoing randomised controlled trial evaluating outpatient management for Home-NPPV will clarify the role of in- and outpatient care for the next future [47].

Conclusion

Based on the available scientific evidence, patients with symptomatic COPD and stable chronic hypercapnic COPD might be considered for additional long-term NPPV treatment (Fig. 1). Improvements in overall survival could be demonstrated when NPPV treatment was targeted to substantially reduce baseline hypercapnia [12]. This strategy was new compared to earlier studies [20-22], where no significant changes in baseline hypercapnia could be demonstrated. In addition, a COPD-centred rehabilitation programme might further enhance the positive outcomes achieved with Home-NPPV [25]. Patients who experienced an exacerbation with indication for acute NPPV are not automatically candidates for Home-NPPV. Some patients might recover from hypercapnic respiratory failure spontaneously in the weeks after the index-exacerbation. Evidence suggests that only patient cohorts with persistent hypercapnia 2–4 weeks after an acute exacerbation might benefit from Home-NPPV [11].

With the application of higher treatment pressures, oronasal masks became more frequently used. The ventilatory strategy in the larger clinical trials was pressure preset assisted ventilation, as this mode might be best tolerated by patients, and might minimize unintended air leaking during ventilation. Pressure titration should be performed cautiously especially in patients with advanced cardiac insufficiency. New developments can be expected in the future, especially with regard to the most suitable health care structures and telemedicine techniques.

Conflict of Interest Statement

Thomas Köhnlein has received speaking fees from Chiesi, AstraZeneca, GSK, Berlin-Chemie, Novartis, Grifols, CSL-Behring. No other conflicts of interest in this work. Sarah Bettina Schwarz has received speaking fees from companies dealing with mechanical ventilation products and travel grants from Löwenstein Medical Germany and from Philips Respironics/USA. No other conflicts of interest in this work. Stephan Nagel has no conflicts of interest to declare. Wolfram Windisch has received speaking fees from companies dealing with mechanical ventilation products. No other conflicts of interest in this work. The Cologne study group (Wolfram Windisch, Sarah Bettina Schwarz) has received open research grants from Weinmann/Germany, Vivisol/Germany, Löwenstein Medical/Germany, VitalAire/Germany, and Philips Respironics/USA.

Funding Sources

This research did not receive grants from any funding agency in the public, commercial or not-for-profit sectors.

Author Contributions

Thomas Köhnlein and Wolfram Windisch were primarily involved in conceptualizing and writing. Thomas Köhnlein and Stephan Nagel contributed to physiologic background and patient selection. Sarah Bettina Schwarz and Wolfram Windisch contributed to technical aspects and ventilation strategy. Thomas Köhnlein and Sarah Bettina Schwarz completed abstract and conclusion. All authors corrected the initial draft of the manuscript. All authors are fully responsible for all content, were involved in all stages of development of the manuscript, and have approved the final version.

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.