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Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial

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Summary

Background

Evidence is weak for the ability of long-term non-invasive positive pressure ventilation (NPPV) to improve survival in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD). Previous prospective studies did not target a reduction in hypercapnia when adjusting ventilator settings. This study investigated the effect of long-term NPPV, targeted to markedly reduce hypercapnia, on survival in patients with advanced, stable hypercapnic COPD.

Methods

This investigator-initiated, prospective, multicentre, randomised, controlled clinical trial enrolled patients with stable GOLD stage IV COPD and a partial carbon dioxide pressure (PaCO2) of 7 kPa (51·9 mm Hg) or higher and pH higher than 7·35. NPPV was targeted to reduce baseline PaCO2 by at least 20% or to achieve PaCO2 values lower than 6·5 kPa (48·1 mm Hg). Patients were randomly assigned (in a 1:1 ratio) via a computer-generated randomisation sequence with a block size of four, to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 months (intervention group). The primary outcome was 1-year all-cause mortality. Analysis was by intention to treat. The intervention was unblinded, but outcome assessment was blinded to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT00710541.

Findings

Patients were recruited from 36 respiratory units in Germany and Austria, starting on Oct 29, 2004, and terminated with a record of the vital status on July 31, 2011. 195 patients were randomly assigned to the NPPV group (n=102) or to the control group (n=93). All patients from the control group and the NPPV group were included in the primary analysis. 1-year mortality was 12% (12 of 102 patients) in the intervention group and 33% (31 of 93 patients) in the control group; hazard ratio 0·24 (95% CI 0·11–0·49; p=0·0004). 14 (14%) patients reported facial skin rash, which could be managed by changing the type of the mask. No other intervention-related adverse events were reported.

Interpretation

The addition of long-term NPPV to standard treatment improves survival of patients with hypercapnic, stable COPD when NPPV is targeted to greatly reduce hypercapnia.

Funding

German Lung Foundation; ResMed, Germany; Tyco Healthcare, Germany; and Weinmann, Germany.

Introduction

Advanced-stage chronic obstructive pulmonary disease (COPD) is characterised by severe bronchial obstruction, pulmonary hyperinflation, and chronic ventilatory failure. Ventilatory failure is thought to be a result of respiratory muscle insufficiency1 and alterations in central ventilatory control.2 The consequences of ventilatory failure are chronic hypercapnia and (compensated) respiratory acidosis. Previous studies suggest that chronic hypercapnic respiratory failure is inversely associated with overall prognosis.3

In patients with chronic hypercapnic respiratory failure, long-term non-invasive positive pressure ventilation (NPPV) has been shown to improve important physiological variables such as blood gases and lung hyperinflation.4 Results from clinical studies showed improvements in exercise capacity (6-min walk distance,5 exercise-related dyspnoea,6 pulmonary cachexia,7 and sleep quality8).Furthermore, disease-specific aspects of health-related quality of life (HRQL) reportedly improve in patients with COPD following long-term NPPV.9 Additionally, NPPV treatment might be associated with fewer hospital admissions and lower overall treatment costs.10

Despite these positive indicators, large randomised trials have failed to document survival benefits when NPPV was added to long-term oxygen treatment compared with long-term oxygen treatment alone.11, 12 Results from the most recent randomised trial showed a small survival benefit, but this benefit was at the cost of worsened HRQL.13 However, NPPV in these studies was done using quite low inspiratory pressures and therefore did not improve hypercapnia. The best results with long-term NPPV have been noted in studies using more intensive forms of NPPV, with higher inspiratory pressures and high backup frequencies that improved or even normalised hypercapnia.14 The effects of such an approach to NPPV on patient survival has yet to be determined.

This study investigated the effect of long-term NPPV, targeted to markedly reduce hypercapnia, on outcomes in patients with advanced COPD with chronic hypercapnic respiratory failure receiving optimised standard treatment.15

Section snippets

Study design and patients

This was an investigator-initiated, multicentre, prospective, randomised, controlled clinical trial using a PROBE design.16 Patients were recruited from 36 respiratory units in Germany and Austria, starting on Oct 29, 2004, and terminated with a record of the vital status on July 31, 2011.

Patients with clinically stable, hypercapnic GOLD stage IV COPD, aged 18 years or older, were eligible for this study if they had a baseline arterial carbon dioxide pressure (PaCO2) of 7 kPa (51·9 mmHg) or

Results

195 (55%) of 352 patients who were referred to a study centre fulfilled all criteria and could be randomly assigned to treatment (figure 1). In August 2010, a national guideline on NPPV treatment was published including recommendations for COPD patients.27 This guideline provided more liberal application criteria for NPPV establishment than those used in this study, and this therefore prevented enrolment of patients into the study and resulted in premature cessation of patient recruitment.

Discussion

The main finding of this study is the positive effect of long-term NPPV on overall survival in patients with hypercapnic, chronic, stable COPD. This survival benefit became evident over 1 year of treatment and seemed to persist thereafter without further increase, although a formal proof of long-term results for more than 1 year was beyond the scope of this study. Additionally, continuous 1-year NPPV treatment was associated with significant improvements in PaCO2, pH, bicarbonate, FEV1, and

References (34)

  • DJ Meecham Jones et al.

    Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD

    Am J Respir Crit Care Med

    (1995)
  • W Windisch

    Impact of home mechanical ventilation on health-related quality of life

    Eur Respir J

    (2008)
  • JM Tuggey et al.

    Domiciliary non-invasive ventilation for recurrent acidotic exacerbations of COPD: an economic analysis

    Thorax

    (2003)
  • E Clini et al.

    The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients

    Eur Respir J

    (2002)
  • RD McEvoy et al.

    Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial

    Thorax

    (2009)
  • M Dreher et al.

    High-intensity versus low-intensity non-invasive ventilation in patients with stable hypercapnic COPD: a randomised crossover trial

    Thorax

    (2010)
  • T Kohnlein et al.

    Multicenter study on “non-invasive ventilation in patients with severe chronic obstructive pulmonary disease and emphysema(COPD)”

    Pneumologie

    (2004)
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