Email updates

Keep up to date with the latest news and content from BMC Medicine and BioMed Central.

Journal App

google play app store
Open Access Review

Admission prevention in COPD: non-pharmacological management

Eui-Sik Suh12*, Swapna Mandal12 and Nicholas Hart123

Author Affiliations

1 Lane Fox Clinical Respiratory Physiology Research Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

2 Division of Asthma, Allergy and Lung Biology, King’s College London, London, UK

3 Lane Fox Respiratory Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

For all author emails, please log on.

BMC Medicine 2013, 11:247  doi:10.1186/1741-7015-11-247


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/11/247


Received:27 August 2013
Accepted:29 October 2013
Published:20 November 2013

© 2013 Suh et al.; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Exacerbations of chronic obstructive pulmonary disease (COPD) are one of the commonest causes of hospital admission in Europe, Australasia, and North America. These adverse events have a large effect on the health status of the patients and impose a heavy burden on healthcare systems. While we acknowledge the contribution of pharmacotherapies to exacerbation prevention, our interpretation of the data is that exacerbations continue to be a major burden to individuals and healthcare systems, therefore, there remains great scope for other therapies to influence exacerbation frequency and preservation of quality of life. In this review, the benefits and limitations of pulmonary rehabilitation, non-invasive ventilation, smoking cessation, and long-term oxygen therapy are discussed. In addition, supported discharge, advanced care coordination, and telehealth programs to improve clinical outcome are reviewed as future directions for the management of COPD.

Please see related article: http://www.biomedcentral.com/1741-7015/11/181 webcite.

Financial and human cost

Management of chronic obstructive pulmonary disease (COPD) is a worldwide challenge. It has a prevalence of 1.5% in the UK [1] and 5.1% in the USA [2], while in China, which has about one-third of the world’s smokers, the prevalence of COPD in patients aged over 40 years is estimated at 8.2% [3]. Current predictions estimate an annual COPD mortality rate in China of over 2 million by 2033 [4]. As expected, COPD imposes a substantial economic burden on healthcare systems. Data from the USA showed that in 1 year, COPD caused 1.5 million emergency department (ED) attendances, 726,000 hospitalizations, and 119,000 deaths [5]. Direct costs of COPD have been estimated at $29.5 billion, with indirect costs of $20.4 billion [6]. Studies in the UK have estimated an annual direct cost of treatment per patient of £819 [7]. Given the heterogeneity of COPD, it is not surprising that acute exacerbations of COPD display a broad range of phenotypes, which can be categorized by their clinical, physiological, radiological, and etiological features [8]. These are discussed in detail in an earlier review on this subject in this journal [9]. Although exacerbation phenotyping can facilitate the targeting of treatments to individual patients, the severity of the exacerbation determines the urgency and location of treatment, and this pragmatic classification is in widespread use (Table 1) [10]. Up to 50% of exacerbations are mild and may go unreported, with 40 to 45% being classified moderate and less than 10% as severe [10].

Table 1. Classification of exacerbation severity[10]

An acute exacerbation of COPD has detrimental effects on lung function [11-14], health-related quality of life (HRQL) [15-17] and exercise capacity [18]. Several studies have shown high mortality rates for patients with COPD who are hospitalized with an acute exacerbation [19-23]. The SUPPORT study reported an in-hospital mortality rate of 11% in patients with COPD admitted with hypercapnic respiratory failure, and 2-year mortality was 49% [23]. Soler-Cataluna et al. demonstrated, in a large Spanish cohort of patients with COPD, the relationship between exacerbation frequency and mortality [19]. Whereas exacerbation-free patients had a survival rate of 80%, patients with three or more exacerbations per year had a 5-year survival rate of only 30%. A recent systematic review of 37 studies involving 189,772 hospitalized patients with COPD reported 12 factors (Table 2) associated with short-term mortality (90 days after hospital discharge) and 9 factors associated with long-term mortality (2 years after hospital discharge) (Table 2) [24].

Table 2. Predictors of early and late mortality in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (adapted from Singanayagam et al.[24])

Hospital admission and re-admission

Intolerable dyspnea is the major cause of hospital admission during an exacerbation of COPD [25]. This event is common, with hospitalization due to dyspnea accounting for one in eight hospital admissions in the UK and one in four admissions in Canada [26]. In the UK, such patients occupy a hospital bed for a median of 5 days [27], with a 20% re-admission rate within 28 days, and up to a third of patients re-admitted within 3 months [27,28]. These data differ from other parts of Europe and from the USA, where 30-day re-admission rate is estimated at 10.9% and 8.1%, respectively [29]. Despite these differences, this is clearly a burden to both healthcare systems and patients, and as of 2011, the UK National Health Service has limited the reimbursement to acute hospitals for patients who are re-admitted within 30 days. Similar key performance targets have been imposed in the USA [30]. Although inhaled and oral drug preparations play an important part in exacerbation prevention, the reduction with pharmacotherapy of severe exacerbations requiring hospitalization is limited. Non-pharmacological management therefore has an important role in the management both of patients with stable disease at risk of exacerbation and of those who are in the immediate recovery phase following an acute exacerbation.

Non-pharmacological management

Pulmonary rehabilitation

Physiological principles

Pulmonary rehabilitation (PR) is ‘an evidence-based, multidisciplinary and comprehensive intervention for patients with COPD that is designed to reduce symptoms, optimize functional status, increase patient participation and reduce healthcare costs through stabilizing or reversing systemic manifestations of the disease’ [31]. Exercise training is a major component of PR, and aims to modify skeletal muscle function to enhance exercise capacity [32,33]. Improved skeletal muscle performance and subsequent reduced lactate production throughout exercise enhances the relationship between respiratory muscle load and respiratory muscle capacity. This is achieved through modifications in breathing pattern, in the context of airflow limitation with optimization of pulmonary mechanics, which reduces exertion-related dyspnea, with a resultant improvement in exercise capacity leading to further improvement in skeletal muscle performance [34,35].

In addition to impaired exercise capacity and disuse in the stable state, several other mechanisms have been implicated in the muscle wasting and weakness associated with exacerbation [36]. Systemic inflammation, confirmed by an elevation in serum interleukin (IL)-6 and IL-8 levels during acute illness, has been shown to have an inverse relationship with quadriceps muscle strength [37]. In addition, oxidative stress is prominent in the peripheral skeletal muscle of patients during an acute exacerbation, which adversely affects mitochondrial function and the contractile properties of the skeletal muscle [38]. Furthermore, blood gas abnormalities affect skeletal muscle function, with hypoxemia being associated with muscle weakness, inhibition of protein synthesis, and activation of proteolysis [39], while hypercapnic acidosis worsens skeletal muscle fatigability [40] and the endurance properties of the diaphragm [41]. Muscle wasting as a consequence of systemic corticosteroid treatment through the inhibition of protein synthesis, downregulation of the anabolic insulin-like growth factor-1 pathway, and activation of catabolic pathways, combined with appetite suppression and reduced dietary intake due to systemic inflammation during acute illness, drives the energy imbalance between supply and demand [42].

Although exercise training plays an important role in improving patient outcomes in COPD, other components contribute significantly to the benefits of PR. PR also addresses the nutritional deficits that are common in stable COPD and during acute exacerbations [43]. Low body mass index is associated with poor prognosis in patients with COPD [44], and caloric supplementation may help to maintain or restore body weight and fat mass, and ensure adequate protein intake. The patient education component of PR is aimed at self-management and enhanced autonomy, in order to encourage early self-identification and treatment of exacerbations. Education programs may also include breathing strategies to control dyspnea as well as bronchial hygiene techniques [43]. Psychosocial support may help to address the anxiety, depression, and other mental health problems that are often associated with chronic respiratory disease [45,46].

Pulmonary rehabilitation delivered in the post-acute exacerbation recovery stage

Although well established as part of chronic care in stable COPD [43,47], there is mounting evidence for the utility of PR in the early recovery period following an exacerbation [48]. Furthermore, data support the role of PR in preventing exacerbations and in reducing acute healthcare utilization, including unscheduled physician visits, ED attendances, and hospital admissions [49]. There are specific features of acute exacerbations that make them an important target for PR. Skeletal muscle dysfunction is evident, with a decline in quadriceps muscle strength of 5% between day 3 and 8 of hospital admission [37]. In the absence of any intervention, quadriceps force continues to decline for up to 3 months after hospital discharge [50]. Immobility and reduced physical activity are major contributors to muscle wasting and weakness, with hospitalized patients spending less than 10 minutes per day walking [51]. Furthermore, these patients remain inactive for up to 1 month after discharge compared with patients with stable COPD and similar disease severity.

Patients are at high risk of re-exacerbation and re-admission in the early recovery phase. Therefore, there is a potential role for an intervention in the post-exacerbation period after an acute episode to reduce the re-admission risk. A recent Cochrane systematic review of five randomized controlled trials (RCTs) of early PR post-acute exacerbation [48] concluded that there was a significant reduction in hospital admissions in patients enrolled in PR programs following an exacerbation (odds ratio 0.22, 95% confidence interval 0.08 to 0.58). More importantly, these data showed that only four patients need to receive PR in the post-acute phase in order to prevent one re-admission, with an overall reduction in mortality observed also (OR 0.28; CI 0.10 to 0.84). There were no serious adverse events in any of the five studies reviewed. Although Eaton et al. showed only a trend towards a reduction in 90-day re-admission in the PR group compared with the usual care (UC) group (23% versus 32%, respectively), the adherence to the PR program was only 40% [52]. However, in the trial of Seymour et al., the effect of early outpatient PR on 3-month re-admission rate was investigated in patients enrolled within 1 week of hospital discharge [50]. The intervention group in this study received 16 exercise training sessions over a 3 month period rather than the standard PR approach of 2 sessions per week for 8 weeks. This ensured that the effect of the treatment was tested, whereas the results of the trial by Eaton et al.[52] were, in part, a consequence of the failure of delivery of the treatment rather than necessarily a failure of the treatment itself. In the Seymour study, re-admission rate at 3 months was lower in the early PR group compared with the UC group (7% versus 33%, respectively; P = 0.02) [50]. Interestingly, Seymour et al. reported that the rate of ED attendances not requiring admission were similar between the two groups, but the rate of hospital attendance of any type was lower in the early PR group (27% versus 57%; P = 0.02). The post-discharge frequency of exacerbations was lower in the early PR group (0.27 versus 1.1; P < 0.01). Although informative, these trials were limited by a relatively short-term follow-up period. By contrast, Ko et al. investigated the effect on healthcare utilization at 12 months of an 8-week program of supervised outpatient PR in patients enrolled up to 3 weeks following hospital discharge [53]. Although the PR group showed improvement in health status at 3 and 6 months, this effect did not persist at 12 months, and there was no reduction in healthcare utilization at 12 months. Similarly, Puhan et al. reported, albeit in an underpowered study, that early PR failed to improve exacerbation rate at 18 months [54]. This is not surprising as the patients enrolled in such trials have severe and very severe COPD, and the interventions that are applied are unlikely to have effect on long-term benefit as the disease process progresses. Despite this, the short-term gains to the patient and acute healthcare providers are clear. In the future, we may target these patients during the exacerbation as inpatients. Acknowledging that these patients have very high levels of dyspnea during this period, which prevents exercise, novel use of technologies that accommodate for or modify dyspnea, such as neuromuscular electrical stimulation [55] and non-invasive ventilation [56], have been used as adjuncts to exercise training in pilot studies, but further work is required.

Pulmonary rehabilitation delivered in the stable state

Although uncontrolled cohort studies have found that PR reduces hospitalization frequency [57,58] and hospital bed days [57-60], RCTs of PR in patients with stable COPD have not shown such consistent results. Griffith et al. reported that despite fewer hospital bed days, there was no reduction in hospitalization frequency in the PR group [61]. Guell et al. found a reduction in hospital admissions over a 2-year period [62]; however, other studies have failed to show a reduction admission frequency and hospital bed days [63,64]. These contrasting data highlight the differing phenotypes of COPD, based on exacerbation frequency, and the requirement for clinicians to develop strategies to target the timing of PR based on the phenotype rather than on the current clinical state of the patient at the time of starting PR.

Non-invasive ventilation

Non-invasive ventilation (NIV) is well established as the treatment of choice for patients with COPD with acute decompensated hypercapnic respiratory failure (AHRF) who fail to respond to standard medical therapy [65,66]. Importantly, and in addition to a reduction in mortality, hospital length of stay is reduced compared with standard treatment. Although NIV remains controversial as a domiciliary treatment to reduce hospital admission and improve survival in patients with COPD with stable chronic respiratory failure, the physiological mechanisms by which long-term NIV results in clinical improvement in patients with severe COPD and hypercapnic respiratory failure are well-described [67]. Indeed, Nickol et al. showed that 3 months of NIV enhanced gas exchange through alterations in pulmonary mechanics (shown as reduced gas trapping), and also increased ventilatory sensitivity to carbon dioxide. However, there was limited effect on non-volitional muscle strength [68]. Clinical manifestations of these physiological changes are reflected as reduced dyspnea and improved HRQL, and it is hypothesized that there will be an associated reduction in acute exacerbations and hospitalization, with a potential for improved survival. However, trial data are as yet inconclusive for this high-risk group of patients with severe COPD.

An observational study from Tuggey et al. showed that, following initiation of domiciliary NIV in a cohort of patients with COPD who were prone to recurrent admissions, there was a significant reduction in total hospital days and days spent in the intensive care unit. This was, not unexpectedly, associated with substantial cost savings [69]. This is in contrast to several RCTs that have failed to show a convincing benefit in terms of acute healthcare utilization. In the trial by Casanova et al., there was no difference in survival between patients with stable COPD randomized to NIV or UC [70], although the proportion of patients who required hospital admission at 3 months was reduced in the intervention group (5% versus 15%; P < 0.05, respectively). Unusually, ventilator set-up in this trial was aimed at reducing accessory muscle use and reducing dyspnea, which explains, in part, the low inspiratory positive airway pressure (IPAP) of 12 cm H2O applied. Clini et al. randomized 90 patients to long-term oxygen therapy (LTOT) alone or home NIV (IPAP 14 cm H2O) with LTOT, as part of a multicentre trial [71]. Adherence to NIV was high in this study at 9 hours per day, but there was only a trend to a reduction in hospital admission comparing admission rate before and after enrolment (45% decrease in hospital admissions in the intervention group versus 27% increase in the UC group). More recently, McEvoy et al. found a significant improvement in survival in a combined NIV and LTOT group in both intention-to-treat and per-protocol (>4 hours NIV use per night) analyses (HR 0.63, 95% CI 0.40 to 0.99, P = 0.045 and HR 0.57, CI 0.33 to 0.96, P = 0.036, respectively) [72]. This was achieved with an adherence of 4.3 hours per night. Despite this beneficial effect, NIV in addition to LTOT treatment conferred no benefit in terms of HRQL or hospital admission, albeit the IPAP in this trial was again low, at 12.9 cm H2O.

Patients with COPD are at greatest risk of death and re-admission immediately after an episode of AHRF. Indeed, the reported re-admission rate is 79.9% with a 1-year mortality rate of 49.1% [73]. Two recent trials have focused on this high-risk group [74,75]. In the trial by Cheung et al., patients who had required NIV for AHRF were randomized to domiciliary nocturnal NIV or continuous positive airway pressure (CPAP) of 5 cm H2O. The intervention was shown to have a lower rate of recurrent AHRF compared with the control group (38.5% versus 60.2%; P = 0.039, respectively) and a longer median time to first re-admission (71 days versus 56 days; P = 0.048, respectively) [74]. CPAP as an appropriate control arm in patients with COPD is interesting. The methodological aim was to balance the possible negative physiological effects of CPAP in patients with severe COPD against the concerns about using a control group that were not exposed to a mask interface. The use of interface with minimal pressure delivery allowed testing of the hypothesis that NIV is beneficial in COPD patients with post-acute hypercapnic respiratory failure. In a separate trial, Funk et al. enrolled patients who had required NIV for AHRF, but randomized the patients, after a run-in period on NIV of 6 months, to either continuation or withdrawal of NIV. The primary endpoint was escalation of ventilation. They found that the rate of ventilation escalation was lower in the NIV continuation group compared with the withdrawal group (15% versus 77%; P = 0.0048, respectively) [75]. These studies suggest a benefit of using domiciliary NIV in patients who are recovering from a recent acute exacerbation complicated by acute hypercapnic respiratory failure.

At present, there is controversy about the use of domiciliary NIV, and there are currently no widely accepted criteria for commencing domiciliary NIV in stable COPD, despite the practice being widespread [76]. The available data indicate that patient selection is important. Specifically, the patients most likely to benefit from long-term domiciliary NIV are those who exhibit symptomatic chronic hypercapnic respiratory failure and those with severe episodes of acute exacerbation requiring acute NIV during hospital admission [77]. Because the prognosis is better for patients who have hypercapnia that is reversible during the post-exacerbation recovery phase [78,79], it is important to target long-term NIV to patients who remain hypercapnic following their acute episode, as shown by the studies of Cheung et al. and Funk et al.[74,75]. Preliminary screening data in 25 patients from a UK RCT of post-exacerbation domiciliary NIV suggest a prevalence of persistent severe hypercapnia (arterial partial pressure of carbon dioxide > 7 kPa 2 weeks after an episode of AHRF) of over 40% [80]. However, further studies are needed to elucidate the trajectory of hypercapnia in a large cohort of patients with COPD treated with acute NIV.

Two RCTs are ongoing in the UK [81] and the Netherlands [82] to establish the effect of domiciliary NIV in reducing mortality and hospital admission for patients with COPD who are hypercapnic. The UK trial is focused on patients following an acute hospital admission requiring NIV, and the trial from the Netherlands is focused on patients with stable COPD who are hypercapnic. There are, however, several challenges in conducting such studies. Firstly, the absence of a true placebo for NIV makes it difficult to have a robust control group for comparison. Most studies to date have compared NIV with UC, with or without LTOT [70-72,75], but a limitation of this approach is that it does not take into account the placebo effects of being given a mask interface. Cheung et al. attempted to address this by administering nasal CPAP at 5 cm H2O to patients in the control group [74]. However, as the authors acknowledged, the possibility remained that the CPAP had a beneficial physiological effect on the control group, and could not therefore be considered to be a true placebo [83,84]. Secondly, the interpretation of the potential benefits of NIV are hampered by relatively short follow-up periods in the trials published to date; only two studies [71,72] have followed patients up for 2 years or more. Clearly, as patients established on domiciliary NIV are likely to remain on it for several years, it would seem advantageous for future studies to assess its benefits over the longer term.

Smoking cessation

Smoking cessation is one of the few interventions shown to reduce mortality in patients with COPD. However, there are relatively few data showing the benefits of smoking cessation in reducing exacerbations. In the Lung Health Study, there was no significant difference in the risk of hospital admission between current smokers and ex-smokers [85]. Furthermore, Kessler et al. reported that smoking status had no effect on hospitalization risk [86], and Garcia-Aymerich et al. showed that current smoking was associated with a reduced risk of hospitalization in a small cohort of patients with COPD [87], suggesting that patients with very advanced disease and high risk of hospital admission quit tobacco consumption as a result of their significant symptom load. By contrast, Godtfredson et al. reported that, in a large prospective population study in Denmark, previous smokers had a lower risk of hospitalization for COPD (HR 0.57, 95% CI 0.73 to 1.18) compared with current smokers [88]. Interestingly, tobacco consumption (low versus high) had no effect on hospital admission. This study is supported by a population study by Au et al., who reported a reduced risk of COPD exacerbations in ex-smokers compared with current smokers when adjusted for comorbidity, markers of COPD severity, and socioeconomic status (adjusted HR 0.78, 95% CI 0.75 to 0.87) [89]. Importantly, the duration of smoking abstinence significantly influenced the magnitude of the reduced exacerbation risk.

Long-term oxygen therapy

Although LTOT is well established as a treatment to improve survival in patients with COPD and hypoxemia, there was no effect on exacerbation or hospitalization rates in early studies [90,91]. The benefits of LTOT in reducing acute healthcare utilization have been shown in the EFRAM cohort, with appropriate LTOT utilization being associated with lower risk of admission [87]. Further evidence was given by Ringbaek et al., who showed in a Danish COPD cohort that LTOT reduced admission rates and hospital days by 23.8% and 31.2%, respectively [92].

Risk stratification and physiological monitoring

Early recognition and treatment of exacerbations, and timely detection of treatment failure during an exacerbation are key factors that may reduce in hospital admissions, facilitate early discharge, and avoid re-admissions. The development of clinical tools to achieve this should be a priority for COPD research. Although there has been a considerable focus on molecular biomarkers, the predictive value of the data has been disappointing [93]. However, more encouraging data have shown that fibrinogen levels, as a biomarker of severity of systemic inflammation, combined with forced expiratory volume in 1 second (FEV1) predicted moderate to severe exacerbations in the following year [94].

Despite the limited clinical usefulness of the molecular biomarkers, basic and advanced physiological measurements have been shown to have increased utility in monitoring the course of COPD. Stevenson et al. showed that inspiratory capacity, as a marker of dynamic hyperinflation, changed significantly during the course of recovery from an exacerbation, while the impedance of the respiratory system, as measured by impulse oscillometry, was unchanged [95]. Murphy et al. investigated the use of a novel technique using electromyography of the second intercostal space parasternal muscle as an advanced physiological biomarker of neural respiratory drive in patients with COPD admitted to hospital with an exacerbation. Indices of neural respiratory drive were shown to be superior to standard bedside clinical measures and spirometry in detecting clinical deterioration [96]. Furthermore, when the neural respiratory drive between admission and discharge were compared, this physiological biomarker had the sensitivity and specificity to identify those patients who were re-admitted within 14 days. Advanced physiological technology that monitors the clinical status of the patient during hospital admission will not only identify treatment failure early but will also allow risk stratification for early re-admission. Furthermore, the technology has the potential to be used as part of a home telehealthcare program.

Supported discharge and telehealth programs

Supported discharge and hospital-at-home programs have been introduced to improve the quality of life of patients by reducing hospital attendance and admission. This has potential benefits both for the patient and for reducing the expenditure within acute healthcare organizations. Studies have shown that in patients with uncomplicated acute exacerbations, early supported discharge is safe, and reduces length of stay without an increased re-admission rate, which was an initial clinical concern [97,98]. However, a meta-analysis of hospital at-home programs, as an alternative to continued hospitalization, concluded from eight trials that there was only a small benefit in terms of re-admission risk (risk ratio 0.76, 95% CI 0.59 to 0.99, P = 0.006) [99]. Furthermore, only a third of all patients were eligible for enrolment in the program, and there was no significant reduction in mortality (RR 0.65, 95% CI 0.4 to 1.04). Importantly, there was also no evidence of a cost saving.

With advances in information technology, advanced care coordination telehealth systems have been developed. These aim to facilitate transfer of clinical data about the patient through telecommunication networks. These data are reviewed remotely by a trained healthcare professional, who provides advice on the basis of the transmitted data [100]. In patients with COPD, such systems are aimed at early recognition and treatment of exacerbations in order to reduce healthcare utilization through admission avoidance, which will be reflected as an enhanced quality of life for the patient [100]. Although bodies such as the European Commission have highlighted the potential of telehealth in the management of chronic diseases, there is limited evidence for its effectiveness in COPD [101]. Although systematic reviews investigating the role of telehealth in patients with COPD have reported reductions in ED attendance and hospital admission [100,102,103], there has been a wide variation in the nature of the interventions themselves, with some of the studies being underpowered [102], such that clinical effectiveness has not been established. A meta-analysis reported that telemonitoring actually appeared to increase the mortality rate compared with UC, suggesting that patients may have delayed seeking urgent medical attention because of false reassurance from the remote assistance [103]. The Whole System Demonstrator study, a UK project funded by the Department of Health, was designed to establish whether integrated care supported by telehealthcare was effective in reducing healthcare utilization and mortality in a large number of patients with chronic illness, including COPD [104]. Primary care practices were randomized to provide either telehealth or UC, and patients were enrolled across three UK regions. Telehealth reduced the hospital admission and mortality [104], but interestingly, there was no improvement in either quality of life or psychological outcomes [105]. In a subsequent economic analysis, telehealth was not shown to be cost-effective in patients with COPD [106]. The results of a large UK RCT in patients with COPD are awaited [107]. In the interim, as part of a European Commission Innovation Partnership project, clinicians, researchers and engineers are working together identify the specific technological, physiological, behavioral, and clinical components that should be included in an advanced care coordination and telehealth deployment program to provide the most benefit to patients [108].

Conclusions

Attention has been focused on the development of non-pharmacological strategies to improve health status and quality of life, and to reduce healthcare utilization and costs by preventing the frequency and severity of acute exacerbations of COPD. These non-pharmacological strategies, although they show potential, need further supporting data before widespread implementation can be suggested.

Abbreviations

AHRF: Acute hypercapnic respiratory failure; COPD: Chronic obstructive pulmonary disease; CPAP: Continuous positive airway pressure; FEV1: Forced expiratory volume in 1 second; HRQL: Health-related quality of life; IL: Interleukin; IPAP: Inspiratory positive airway pressure; LTOT: Long-term oxygen therapy; NIV: Non-invasive ventilation; PR: Pulmonary rehabilitation; RCT: Randomised controlled trial; UC: Usual care.

Competing interests

NH is in receipt of a European Union grant for the development of care coordination and telehealthcare for chronic diseases including COPD. ES is in receipt of an unrestricted educational grant from Philips Electronics to develop advanced physiological monitoring techniques in patients with COPD.

Authors’ contributions

ES, SM, and NH contributed to the literature review and manuscript preparation. All authors have read and approved the final manuscript.

Acknowledgements

We gratefully acknowledge funding from Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, NIHR Comprehensive Biomedical Research Centre, London, UK (to NH); from Guy’s and St Thomas’ Charity (to ES and SM); and from Philips Research (to ES).

References

  1. White P: Prevalence of COPD in primary care: no room for complacency.

    Fam Pract 2009, 26:1-2. PubMed Abstract | Publisher Full Text OpenURL

  2. Akinbami LJ, Liu X: Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998–2009.

    NCHS Data Brief 2011, 63:1-8. PubMed Abstract OpenURL

  3. Zhong N, Wang C, Yao W, Chen P, Kang J, Huang S, Chen B, Wang C, Ni D, Zhou Y, et al.: Prevalence of chronic obstructive pulmonary disease in China: a large, population-based survey.

    Am J Respir Crit Care Med 2007, 176:753-760. PubMed Abstract | Publisher Full Text OpenURL

  4. Lin H-H, Murray M, Cohen T, Colijn C, Ezzati M: Effects of smoking and solid-fuel use on COPD, lung cancer, and tuberculosis in China: a time-based, multiple risk factor, modelling study.

    The Lancet 2008, 372:1473-1483. Publisher Full Text OpenURL

  5. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC: Chronic obstructive pulmonary disease surveillance–United States, 1971–2000.

    MMWR Surveill Summ 2002, 51:1-16. PubMed Abstract OpenURL

  6. National Heart, Lung and Blood Institute. Morbidity and Mortality: 2009 Chartbook of Cardiovascular, Lung and Blood Diseases. Bethesda (MD): National Institutes of Health; 2009. OpenURL

  7. National Collaborating Centre for Chronic Conditions: Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care.

    Thorax 2004, 59:1-232. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  8. Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, et al.: Chronic obstructive pulmonary disease phenotypes: the future of COPD.

    Am J Respir Crit Care Med 2010, 182:598-604. PubMed Abstract | Publisher Full Text OpenURL

  9. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC: Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease.

    BMC Med 2013, 11:181. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  10. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, et al.: Outcomes for COPD pharmacological trials: from lung function to biomarkers.

    Eur Respir J 2008, 31:416-469. PubMed Abstract | Publisher Full Text OpenURL

  11. Donaldson GC, Seemungal TA, Patel IS, Bhowmik A, Wilkinson TM, Hurst JR, Maccallum PK, Wedzicha JA: Airway and systemic inflammation and decline in lung function in patients with COPD.

    Chest 2005, 128:1995-2004. PubMed Abstract | Publisher Full Text OpenURL

  12. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA: Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.

    Thorax 2002, 57:847-852. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  13. Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley PMA: Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease.

    Am J Res Crit Care Med 2008, 178:332-338. Publisher Full Text OpenURL

  14. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PMA, Celli B, Coxson HO, Crim C, et al.: Changes in forced expiratory volume in 1 second over time in COPD.

    N Eng J Med 2011, 365:1184-1192. Publisher Full Text OpenURL

  15. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA: Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.

    Am J Respir Crit Care Med 1998, 157:1418-1422. PubMed Abstract | Publisher Full Text OpenURL

  16. Halpin DM, Decramer M, Celli B, Kesten S, Liu D, Tashkin DP: Exacerbation frequency and course of COPD.

    Int J Chron Obstruct Pulmon Dis 2012, 7:653-661. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  17. Esteban C, Quintana JM, Moraza J, Aburto M, Egurrola M, España PP, Pérez-Izquierdo J, Aguirre U, Aizpiri S, Capelastegui A: Impact of hospitalisations for exacerbations of COPD on health-related quality of life.

    Respir Med 2009, 103:1201-1208. PubMed Abstract | Publisher Full Text OpenURL

  18. Cote CG, Dordelly LJ, Celli BR: Impact of COPD exacerbations on patient-centered outcomes.

    Chest 2007, 131:696-704. PubMed Abstract | Publisher Full Text OpenURL

  19. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R: Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.

    Thorax 2005, 60:925-931. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  20. Almagro P, Calbo E, Ochoa De Echaguen A, Barreiro B, Quintana S, Heredia JL, Garau U: Mortality after hospitalization for COPD.

    Chest 2002, 121:1441-1448. PubMed Abstract | Publisher Full Text OpenURL

  21. Groenewegen KH, Schols AM, Wouters EF: Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD.

    Chest 2003, 124:459-467. PubMed Abstract | Publisher Full Text OpenURL

  22. Steer J, Norman EM, Afolabi OA, Gibson GJ, Bourke SC: Dyspnoea severity and pneumonia as predictors of in-hospital mortality and early readmission in acute exacerbations of COPD.

    Thorax 2012, 67:117-121. PubMed Abstract | Publisher Full Text OpenURL

  23. Connors A, Dawson N, Thomas C, Harrell F, Desbiens N, Fulkerson W, Kussin P, Bellamy P, Goldman L, Knaus W: Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (study to understand prognoses and preferences for outcomes and risks of treatments).

    Am J Respir Crit Care Med 1996, 154:959-967. PubMed Abstract | Publisher Full Text OpenURL

  24. Singanayagam A, Schembri S, Chalmers JD: Predictors of mortality in hospitalized adults with acute exacerbation of chronic obstructive pulmonary disease.

    Ann Am Thoracic Soc 2013, 10:81-89. OpenURL

  25. O’Donnell DE, Parker CM: COPD exacerbations. 3: pathophysiology.

    Thorax 2006, 61:354-361. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  26. Gershon AS, Guan J, Victor JC, Goldstein R, To T: Quantifying health services use for chronic obstructive pulmonary disease.

    Am J Respir Crit Care Med 2013, 187:596-601. PubMed Abstract | Publisher Full Text OpenURL

  27. Royal College of Physicians, British Thoracic Society, British Lung Foundation: Report of the national chronic obstructive pulmonary disease audit 2008: clinical audit of COPD exacerbations admitted to acute NHS trusts across the UK. Royal College of Physicians; 2008.

  28. Anstey K, Lowe D, Roberts CM, Hosker H: Report of the 2003 National COPD Audit. London: Royal College of Physicians/British Thoracic Society; 2004. OpenURL

  29. Westert GP, Lagoe RJ, Keskimäki I, Leyland A, Murphy M: An international study of hospital readmissions and related utilization in Europe and the USA.

    Health Policy 2002, 61:269-278. PubMed Abstract | Publisher Full Text OpenURL

  30. Reineck LA, Kahn JM: Quality measurement in the affordable care Act. A reaffirmed commitment to value in health care.

    Am J Res Crit Care Med 2013, 187:1038-1039. Publisher Full Text OpenURL

  31. Nici L, ZuWallack R, Wouters E, Donner CF: On pulmonary rehabilitation and the flight of the bumblebee: the ATS/ERS statement on pulmonary rehabilitation.

    Eur Respir J 2006, 28:461-462. PubMed Abstract | Publisher Full Text OpenURL

  32. Barnes PJ, Celli BR: Systemic manifestations and comorbidities of COPD.

    Eur Respir J 2009, 33:1165-1185. PubMed Abstract | Publisher Full Text OpenURL

  33. Maltais F, Simard AA, Simard C, Jobin J, Desgagnes P, LeBlanc P: Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD.

    Am J Respir Crit Care Med 1996, 153:288-293. PubMed Abstract | Publisher Full Text OpenURL

  34. Porszasz J, Emtner M, Goto S, Somfay A, Whipp BJ, Casaburi R: Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD.

    Chest 2005, 128:2025-2034. PubMed Abstract | Publisher Full Text OpenURL

  35. Hawkins P, Johnson LC, Nikoletou D, Hamnegard CH, Sherwood R, Polkey MI, Moxham J: Proportional assist ventilation as an aid to exercise training in severe chronic obstructive pulmonary disease.

    Thorax 2002, 57:853-859. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  36. Gayan-Ramirez G, Decramer M: Mechanisms of striated muscle dysfunction during acute exacerbations of COPD.

    J App Physiol 2013, 114:1291-1299. Publisher Full Text OpenURL

  37. Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, Bouillon R, Decramer M: Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I.

    Thorax 2003, 58:752-756. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  38. Crul T, Testelmans D, Spruit MA, Troosters T, Gosselink R, Geeraerts I, Decramer M, Gayan-Ramirez G: Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD.

    Cell Physiol Biochem 2010, 25:491-500. PubMed Abstract | Publisher Full Text OpenURL

  39. Kim HC, Mofarrahi M, Hussain SN: Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease.

    Int J Chron Obstruct Pulmon Dis 2008, 3:637-658. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  40. Vianna LG, Koulouris N, Lanigan C, Moxham J: Effect of acute hypercapnia on limb muscle contractility in humans.

    J Appl Physiol 1990, 69:1486-1493. PubMed Abstract | Publisher Full Text OpenURL

  41. Juan G, Calverley P, Talamo C, Schnader J, Roussos C: Effect of carbon dioxide on diaphragmatic function in human beings.

    N Engl J Med 1984, 310:874-879. PubMed Abstract | Publisher Full Text OpenURL

  42. Vermeeren M, Schols A, Wouters E: Effects of an acute exacerbation on nutritional and metabolic profile of patients with COPD.

    Euro Respir J 1997, 10:2264-2269. Publisher Full Text OpenURL

  43. Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B, et al.: American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation.

    Am J Respir Crit Care Med 2006, 173:1390-1413. PubMed Abstract | Publisher Full Text OpenURL

  44. Vestbo J, Prescott E, Almdal T, Dahl M, Nordestgaard BG, Andersen T, Sorensen TI, Lange P: Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study.

    Am J Respir Crit Care Med 2006, 173:79-83. PubMed Abstract | Publisher Full Text OpenURL

  45. Maurer J, Rebbapragada V, Borson S, Goldstein R, Kunik ME, Yohannes AM, Hanania NA: Anxiety and depression in copd: current understanding, unanswered questions, and research needs.

    CHEST Journal 2008, 134:43S-56S. Publisher Full Text OpenURL

  46. Bhandari NJ, Jain T, Marolda C, ZuWallack RL: Comprehensive pulmonary rehabilitation results in clinically meaningful improvements in anxiety and depression in patients with chronic obstructive pulmonary disease.

    J Cardiopulm Rehabil Prev 2013, 33:123-127. PubMed Abstract | Publisher Full Text OpenURL

  47. Lacasse Y, Goldstein R, Lasserson TJ, Martin S: Pulmonary rehabilitation for chronic obstructive pulmonary disease.

    Cochrane Database Syst Rev 2006., 4

    CD003793

    OpenURL

  48. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH, Steurer J: Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease.

    Cochrane Database Syst Rev 2011., 10

    CD005305

    OpenURL

  49. Kon SS, Canavan JL, Man WD: Pulmonary rehabilitation and acute exacerbations of COPD.

    Expert Rev Respir Med 2012, 6:523-531.

    quiz 531

    PubMed Abstract | Publisher Full Text OpenURL

  50. Seymour JM, Moore L, Jolley CJ, Ward K, Creasey J, Steier JS, Yung B, Man WD, Hart N, Polkey MI, et al.: Outpatient pulmonary rehabilitation following acute exacerbations of COPD.

    Thorax 2010, 65:423-428. PubMed Abstract | Publisher Full Text OpenURL

  51. Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R: Physical activity and hospitalization for exacerbation of COPD.

    Chest 2006, 129:536-544. PubMed Abstract | Publisher Full Text OpenURL

  52. Eaton T, Young P, Fergusson W, Moodie L, Zeng I, O’Kane F, Good N, Rhodes L, Poole P, Kolbe J: Does early pulmonary rehabilitation reduce acute health-care utilization in COPD patients admitted with an exacerbation? A randomized controlled study.

    Respirology 2009, 14:230-238. PubMed Abstract | Publisher Full Text OpenURL

  53. Ko FW, Dai DL, Ngai J, Tung A, Ng S, Lai K, Fong R, Lau H, Tam W, Hui DS: Effect of early pulmonary rehabilitation on health care utilization and health status in patients hospitalized with acute exacerbations of COPD.

    Respirology 2011, 16:617-624. PubMed Abstract | Publisher Full Text OpenURL

  54. Puhan MA, Spaar A, Frey M, Turk A, Brandli O, Ritscher D, Achermann E, Kaelin R, Karrer W: Early versus late pulmonary rehabilitation in chronic obstructive pulmonary disease patients with acute exacerbations: a randomized trial.

    Respiration 2012, 83:499-506. PubMed Abstract | Publisher Full Text OpenURL

  55. Maddocks M, Gao W, Higginson IJ, Wilcock A: Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease.

    Cochrane Database Syst Rev 2013., 1

    CD009419

    OpenURL

  56. Dyer F, Flude L, Bazari F, Jolley C, Englebretsen C, Lai D, Polkey MI, Hopkinson NS: Non-invasive ventilation (NIV) as an aid to rehabilitation in acute respiratory disease.

    BMC Pulm Med 2011, 11:58. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  57. Raskin J, Spiegler P, McCusker C, ZuWallack R, Bernstein M, Busby J, DiLauro P, Griffiths K, Haggerty M, Hovey L, et al.: The effect of pulmonary rehabilitation on healthcare utilization in chronic obstructive pulmonary disease: the northeast pulmonary rehabilitation consortium.

    J Cardiopulm Rehabil 2006, 26:231-236. PubMed Abstract | Publisher Full Text OpenURL

  58. Cecins N, Geelhoed E, Jenkins SC: Reduction in hospitalisation following pulmonary rehabilitation in patients with COPD.

    Aust Health Rev 2008, 32:415-422. PubMed Abstract | Publisher Full Text OpenURL

  59. Hui KP, Hewitt AB: A simple pulmonary rehabilitation program improves health outcomes and reduces hospital utilization in patients with COPD.

    Chest 2003, 124:94-97. PubMed Abstract | Publisher Full Text OpenURL

  60. Chakravorty I, Fasakin C, Paine T, Narasimhaiah D, Austin G: Outpatient-based pulmonary rehabilitation for COPD: a cost of illness study.

    ISRN Pulmonol 2011, 2011:6. OpenURL

  61. Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, et al.: Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial.

    Lancet 2000, 355:362-368. PubMed Abstract | Publisher Full Text OpenURL

  62. Guell R, Casan P, Belda J, Sangenis M, Morante F, Guyatt GH, Sanchis J: Long-term effects of outpatient rehabilitation of COPD: a randomized trial.

    Chest 2000, 117:976-983. PubMed Abstract | Publisher Full Text OpenURL

  63. Engstrom CP, Persson LO, Larsson S, Sullivan M: Long-term effects of a pulmonary rehabilitation programme in outpatients with chronic obstructive pulmonary disease: a randomized controlled study.

    Scand J Rehabil Med 1999, 31:207-213. PubMed Abstract | Publisher Full Text OpenURL

  64. Ries AL, Kaplan RM, Limberg TM, Prewitt LM: Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease.

    Ann Intern Med 1995, 122:823-832. PubMed Abstract | Publisher Full Text OpenURL

  65. Plant PK, Owen JL, Elliott MW: Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial.

    Lancet 2000, 355:1931-1935. PubMed Abstract | Publisher Full Text OpenURL

  66. British Thoracic Society, Royal College of Physicians (London), Intensive Care Society: The Use of Non-Invasive Ventilation in the management of patients with chronic obstructive pulmonary disease admitted to hospital with acute type II respiratory failure (with particular reference to Bilevel positive pressure ventilation). London: British Thoracic Society, Royal College of Physicians (London), Intensive Care Society; 2008.

  67. Kallet RH, Diaz JV: The physiologic effects of noninvasive ventilation.

    Respir Care 2009, 54:102-115. PubMed Abstract | Publisher Full Text OpenURL

  68. Nickol AH, Hart N, Hopkinson NS, Hamnegard CH, Moxham J, Simonds A, Polkey MI: Mechanisms of improvement of respiratory failure in patients with COPD treated with NIV.

    Int J Chron Obstruct Pulmon Dis 2008, 3:453-462. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  69. Tuggey JM, Plant PK, Elliott MW: Domiciliary non-invasive ventilation for recurrent acidotic exacerbations of COPD: an economic analysis.

    Thorax 2003, 58:867-871. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  70. Casanova C, Celli BR, Tost L, Soriano E, Abreu J, Velasco V, Santolaria F: Long-term controlled trial of nocturnal nasal positive pressure ventilation in patients with severe COPD.

    Chest 2000, 118:1582-1590. PubMed Abstract | Publisher Full Text OpenURL

  71. Clini E, Sturani C, Rossi A, Viaggi S, Corrado A, Donner CF, Ambrosino N: The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients.

    Eur Respir J 2002, 20:529-538. PubMed Abstract | Publisher Full Text OpenURL

  72. McEvoy RD, Pierce RJ, Hillman D, Esterman A, Ellis EE, Catcheside PG, O’Donoghue FJ, Barnes DJ, Grunstein RR: Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial.

    Thorax 2009, 64:561-566. PubMed Abstract | Publisher Full Text OpenURL

  73. Chu CM, Chan VL, Lin AW, Wong IW, Leung WS, Lai CK: Readmission rates and life threatening events in COPD survivors treated with non-invasive ventilation for acute hypercapnic respiratory failure.

    Thorax 2004, 59:1020-1025. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  74. Cheung AP, Chan VL, Liong JT, Lam JY, Leung WS, Lin A, Chu CM: A pilot trial of non-invasive home ventilation after acidotic respiratory failure in chronic obstructive pulmonary disease.

    Int J Tuberc Lung Dis 2010, 14:642-649. PubMed Abstract | Publisher Full Text OpenURL

  75. Funk GC, Breyer MK, Burghuber OC, Kink E, Kirchheiner K, Kohansal R, Schmidt I, Hartl S: Long-term non-invasive ventilation in COPD after acute-on-chronic respiratory failure.

    Respir Med 2011, 105:427-434. PubMed Abstract | Publisher Full Text OpenURL

  76. Lloyd-Owen SJ, Donaldson GC, Ambrosino N, Escarabill J, Farre R, Fauroux B, Robert D, Schoenhofer B, Simonds AK, Wedzicha JA: Patterns of home mechanical ventilation use in Europe: results from the Eurovent survey.

    Eur Respir J 2005, 25:1025-1031. PubMed Abstract | Publisher Full Text OpenURL

  77. NAMDRC: 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 1999, 116:521-534. PubMed Abstract | Publisher Full Text OpenURL

  78. Costello R, Deegan P, Fitzpatrick M, McNicholas WT: Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis.

    Am J Med 1997, 102:239-244. PubMed Abstract | Publisher Full Text OpenURL

  79. McNally E, Fitzpatrick M, Bourke S, Costello R, McNicholas WT: Reversible hypercapnia in acute exacerbations of chronic obstructive pulmonary disease (COPD).

    Eur Respir J 1993, 6:1353-1356. PubMed Abstract OpenURL

  80. Murphy P, Gibson GJ, Polkey MI, Hart N: HOT HMV UK: prevalence of persistent significant hypercapnia following acute exacerbation of COPD (AECOPD) requiring non-invasive ventilation (NIV) [Abstract].

    Thorax 2010, 65:A33. OpenURL

  81. http://www.clinicaltrials.gov NCT00990132

  82. http://www.trialregister.nl NTR1100

  83. Miro AM, Shivaram U, Hertig I: COntinuous positive airway pressure in copd patients in acute hypercapnic respiratory failure.

    CHEST Journal 1993, 103:266-268. Publisher Full Text OpenURL

  84. Goldberg P, Reissmann H, Maltais F, Ranieri M, Gottfried SB: Efficacy of noninvasive CPAP in COPD with acute respiratory failure.

    Eur Respir J 1995, 8:1894-1900. PubMed Abstract | Publisher Full Text OpenURL

  85. Anthonisen NR, Connett JE, Enright PL, Manfreda J: Lung health study research G: hospitalizations and mortality in the lung health study.

    Am J Respir Crit Care Med 2002, 166:333-339. PubMed Abstract | Publisher Full Text OpenURL

  86. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E: Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease.

    Am J Respir Crit Care Med 1999, 159:158-164. PubMed Abstract | Publisher Full Text OpenURL

  87. Garcia-Aymerich J, Monso E, Marrades RM, Escarrabill J, Felez MA, Sunyer J, Anto JM: Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation.

    Am J Respir Crit Care Med 2001, 164:1002-1007. PubMed Abstract | Publisher Full Text OpenURL

  88. Godtfredsen NS, Vestbo J, Osler M, Prescott E: Risk of hospital admission for COPD following smoking cessation and reduction: a Danish population study.

    Thorax 2002, 57:967-972. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  89. Au DH, Bryson CL, Chien JW, Sun H, Udris EM, Evans LE, Bradley KA: The effects of smoking cessation on the risk of chronic obstructive pulmonary disease exacerbations.

    J Gen Intern Med 2009, 24:457-463. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  90. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party

    Lancet 1981, 1:681-686. PubMed Abstract | Publisher Full Text OpenURL

  91. Is 12-hour oxygen as effective as 24-hour oxygen in advanced chronic obstructive pulmonary disease with hypoxemia? (The Nocturnal Oxygen Therapy Trial–NOTT)

    Chest 1980, 78:419-420. PubMed Abstract | Publisher Full Text OpenURL

  92. Ringbaek TJ, Viskum K, Lange P: Does long-term oxygen therapy reduce hospitalisation in hypoxaemic chronic obstructive pulmonary disease?

    Eur Respir J 2002, 20:38-42. PubMed Abstract | Publisher Full Text OpenURL

  93. Hurst JR, Donaldson GC, Perera WR, Wilkinson TM, Bilello JA, Hagan GW, Vessey RS, Wedzicha JA: Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.

    Am J Respir Crit Care Med 2006, 174:867-874. PubMed Abstract | Publisher Full Text OpenURL

  94. Rosenberg SR, Kalhan R: Biomarkers in chronic obstructive pulmonary disease.

    Translational Res 2012, 159:228-237. Publisher Full Text OpenURL

  95. Stevenson NJ, Walker PP, Costello RW, Calverley PMA: Lung mechanics and dyspnea during exacerbations of chronic obstructive pulmonary disease.

    Am J Respir Crit Care Med 2005, 172:1510-1516. PubMed Abstract | Publisher Full Text OpenURL

  96. Murphy PB, Kumar A, Reilly C, Jolley C, Walterspacher S, Fedele F, Hopkinson NS, Man WD, Polkey MI, Moxham J, et al.: Neural respiratory drive as a physiological biomarker to monitor change during acute exacerbations of COPD.

    Thorax 2011, 66:602-608. PubMed Abstract | Publisher Full Text OpenURL

  97. Cotton MM, Bucknall CE, Dagg KD, Johnson MK, MacGregor G, Stewart C, Stevenson RD: Early discharge for patients with exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial.

    Thorax 2000, 55:902-906. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  98. Skwarska E, Cohen G, Skwarski KM, Lamb C, Bushell D, Parker S, MacNee W: Randomized controlled trial of supported discharge in patients with exacerbations of chronic obstructive pulmonary disease.

    Thorax 2000, 55:907-912. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  99. Jeppesen E, Brurberg KG, Vist GE, Wedzicha JA, Wright JJ, Greenstone M, Walters JA: Hospital at home for acute exacerbations of chronic obstructive pulmonary disease.

    Cochrane Database Syst Rev 2012., 5

    CD003573

    OpenURL

  100. McLean S, Nurmatov U, Liu JL, Pagliari C, Car J, Sheikh A: Telehealthcare for chronic obstructive pulmonary disease.

    Cochrane Database Syst Rev 2011., 7

    CD007718

    OpenURL

  101. McKinstry B, Pinnock H, Sheikh A: Telemedicine for management of patients with COPD?

    Lancet 2009, 374:672-673. PubMed Abstract | Publisher Full Text OpenURL

  102. Bolton CE, Waters CS, Peirce S, Elwyn G: Insufficient evidence of benefit: a systematic review of home telemonitoring for COPD.

    J Eval Clin Prac 2011, 17:1216-1222. Publisher Full Text OpenURL

  103. Polisena J, Tran K, Cimon K, Hutton B, McGill S, Palmer K, Scott RE: Home telehealth for chronic obstructive pulmonary disease: a systematic review and meta-analysis.

    J Telemed Telecare 2010, 16:120-127. PubMed Abstract | Publisher Full Text OpenURL

  104. Steventon A, Bardsley M, Billings J, Dixon J, Doll H, Hirani S, Cartwright M, Rixon L, Knapp M, Henderson C, et al.: Effect of telehealth on use of secondary care and mortality: findings from the whole system demonstrator cluster randomised trial.

    BMJ 2012, 344:e3874. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  105. Cartwright M, Hirani SP, Rixon L, Beynon M, Doll H, Bower P, Bardsley M, Steventon A, Knapp M, Henderson C, et al.: Effect of telehealth on quality of life and psychological outcomes over 12 months (Whole Systems Demonstrator Telehealth Questionnaire Study): nested study of patient reported outcomes in a pragmatic, cluster randomised controlled trial.

    BMJ 2013, 346:f653. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  106. Henderson C, Knapp M, Fernandez JL, Beecham J, Hirani SP, Cartwright M, Rixon L, Beynon M, Rogers A, Bower P, et al.: Cost effectiveness of telehealth for patients with long term conditions (Whole Systems Demonstrator Telehealth Questionnaire Study): nested economic evaluation in a pragmatic, cluster randomised controlled trial.

    BMJ 2013, 346:f1035. PubMed Abstract | Publisher Full Text OpenURL

  107. Pinnock H, Hanley J, Lewis S, MacNee W, Pagliari C, van der Pol M, Sheikh A, McKinstry B: The impact of a telemetric chronic obstructive pulmonary disease monitoring service: randomised controlled trial with economic evaluation and nested qualitative study.

    Prim Care Respir J 2009, 18:233-235. PubMed Abstract | Publisher Full Text OpenURL

  108. Advancing Care Coordination and Telehealth Deployment.

    http://www.act-program.eu/ webcite

    OpenURL