The effect of domiciliary noninvasive ventilation on clinical outcomes in stable and recently hospitalized patients with COPD: a systematic review and meta-analysis

Figures & data

Table 1 Study inclusion criteria

Study design	Patients	Intervention	Comparator
RCTs (parallel or crossover)	Adult COPD	Any form of	Usual care or another
Nonrandomized controlled studies	patients	domiciliary NIV	form of NIV
Systematic reviews (for identifying further primary studies)

Abbreviations: RCTs, randomized controlled trials; NIV, noninvasive ventilation.

Table 2 Main study and intervention characteristics

Study	N (na, % male)	Length of follow-up	Stable or posthospital/post-exacerbation population and proportion on LTOT	Hypercapnia	NIV target	Comparator	Main outcomes
Randomized controlled trials (NIV vs usual care): stable disease
Bhatt et al,^Citation17 USA	30 (20/27a, 74%)	6 months	Stable: no exacerbations in 4 weeks prior to study LTOT: no details	Patients described as normocapnic. Inclusion criterion: PaCO2 <52 mmHg (or <6.93 kPa)	Pressure	Usual care	QoL, adherence, FEV1 % predicted, FVC % predicted, PaCO2, and PaO2
Casanova et al,^Citation19 Spain	52 (43/44a, 98%)	12 months	Stable: no acute exacerbation in previous 3 months LTOT: 93%	No details, but stated in the discussion that: “The number of hypercapnic patients in our series was small”. Mean (SD) PaCO2in NIV group 50.7 (7.9) (or 6.76) kPa and usual care group 53.2 (8.6) (or 7.09) kPa	Pressure	Usual care	Survival, exacerbations, hospitalizations, adherence, FEV1 % predicted, FVC % predicted, PaCO2, and PaO2
Clini et al,^Citation27 Italy	90 (69/86a, 80%)	24 months	Stable clinical condition, as assessed by an arterial pH >7.35, and free from exacerbation in the 4 weeks preceding recruitment LTOT: 100%	Inclusion criterion: PaCO2 >6.6 kPa	Pressure	Usual care	Survival, hospitalizations, QoL, adherence, FEV1 % predicted, PaCO2, PaO2, and 6MWD
Duiverman et al,^Citation20 the Netherlands	72 (35/66a, 53% first study period; 33/56a, 59% second study period)	3 months	Stable clinical condition (no exacerbation in the 4 weeks prior to study participation together with a pH of >7.35) LTOT: 45% (first study period) and 57% (second study period)	Inclusion criterion: PaCO2 >6.0 kPa	Blood gases	Usual care + 12-week multidisciplinary rehabilitation program	QoL, FEV1 % predicted, PaCO2, PaO2, 6MWD
Duiverman et al,^Citation21 the Netherlands		24 months				Usual care + home-based rehabilitation program	Survival, exacerbations, hospitalizations, adherence, FEV1 % predicted, PaCO2, PaO2, and 6MWD
Garrod et al,^Citation18 UK	45 (28/45, 62%)	3 months	Stable severe COPD. Patients had no reported exacerbations in the past 4 weeks LTOT: 4%	Patients described as normocapnic. NIV group mean PaCO2 44.2 (6.68) (or 5.89) kPa. Usual care mean PaCO2 46.1 (9.07) (or 6.15) kPa	Pressure	Usual care + pulmonary rehabilitation program during part of the RCT	Exacerbations, QoL, adherence, FEV1 % predicted, FVC, PaCO2, and PaO2
Gay et al,^Citation51 USA	13 (10/13, 77%)	3 months	Clinically stable, severe COPD. No major changes in FEV1, PaCO2, hospitalization, or change in medications over a 6-week period LTOT: 77%	Inclusion criterion: PaCO2 >45 mmHg (or 6.0 kPa)	Pressure	Usual care	Adherence, FEV1 % predicted, PaCO2, PaO2, and 6MWD
Kamiński et al,^Citation25 Poland	19 (16/19, 84%)	NIV mean 16 (10) months and usual care mean 23 (13) months	Stable: exacerbation of COPD during last 3 months was an exclusion criterion LTOT: 100%	Inclusion criterion: PaCO2 >50 mmHg (or 6.6 kPa)	Blood gases	Usual care	Survival, hospitalizations, adherence, FEV1, FVC, PaCO2, PaO2, and 6MWD
Köhnlein et al,^Citation23 Germany	195 (121/195, 62%)	12 months	Stable: no exacerbations in 4 weeks prior to study LTOT: 65%	Yes (PaCO2) of $7 kPa (51.9 mmHg)	Blood gases	Usual care	Survival, hospitalizations, QoL, adherence, FEV1, FVC, PaCO2, PaO2, and 6MWD
McEvoy et al,^Citation26 Australia	144 (94/144, 65%)	12 months	Stable hypercapnic COPD LTOT: 100%	All described as hypercapnic. PaCO2 >46 mmHg (or 6.13 kPa) at least twice in the previous6 months during periods of clinical stability	Pressure	Usual care	Survival, hospitalizations, QoL, adherence, FEV1 % predicted, FVC, PaCO2, and PaO2
Meecham-Jones et al,^Citation41 UK Crossover RCT	18 (15/18, 83%)	3 months	Stable clinical state for at least 1 month prior to entry into the study, with no recent deterioration in clinical state, spirometric values, or resting blood gases LTOT: 100%	Inclusion criterion: PaCO2 >45 mmHg (or 6.0 kPa)	Pressure	Usual care	QoL, adherence, FEV1, FVC, PaCO2, PaO2, and 6MWD
Sin et al,^Citation52 Canada	23 (10/21a, 48%)	3 months	Advanced stable COPD (no further details) LTOT: proportion unclear	Based on mean PaCO2, NIV 43.1 (4.9) mmHg (or 5.7 kPa) and usual care 45.2 (13.5) mmHg (or 6.0 kPa); a proportion of patients with hypercapnia	Pressure	Usual care	Adherence, FEV1, PaCO2, and 6MWD
Strumpf et al,^Citation53 USA Cross-over RCT	19 (19/23b, 83%)	3 months	Severe, stable COPD. No exacerbation of airway disease within the previous month LTOT: 86% (completers only)	Mean PaCO2 49 (2) mmHg, range 35–67 (range 4.7–8.9 kPa). Likely to include a proportion of patients with hypercapnia	Blood gases	Usual care	Hospitalizations, exacerbations, adherence, FEV1, FVC, PaCO2, and PaO2
Zhou et al,^Citation24 People’s Republic of China	36 (29/36, 81%)	12 months	Stable. No exacerbations within the last month LTOT: 100% usual care arm; no details for NIV arm	Baseline PaCO2 NIV 57.42 (7.64) (or 7.6) kPa and usual care 56.89 (8.26) (or 7.6) kPa. Likely to include proportion of patients with hypercapnia	Pressure	Usual care	Survival, exacerbations, hospitalizations, adherence, PaCO2, PaO2, and pH
Randomized controlled trials (NIV vs usual care): posthospitalization for acute exacerbation
Cheung et al,^Citation31 People’s Republic of China	47 (43/47, 91%)	12 months	Posthospital: patients who were admitted with a severe exacerbation with persistent respiratory acidosis despite initial treatment with bronchodilators, corticosteroids, and antibiotics, and who required treatment with NIV. Those who survived after treatment with acute NIV were the target study population LTOT: 45%	Inclusion criterion: PaCO2 >6 kPa	Volume	Usual care	Survival, exacerbations, hospitalizations, adherence, and PaCO2
De Backer et al,^Citation54 Belgium	15 (10/15, 67%)	6 months	Posthospital: hospitalized due to a hypercapnic exacerbation LTOT: no details	Inclusion criterion: PaCO2 >45 mmHg (or 6.0 kPa)	Blood gases	Usual care	FEV1, PaCO2, and 6MWD
Murphy et al,^Citation55 UK Interim results	36 (no details)	3 months	Posthospital: patients admitted for acute hypercapnic respiratory failure due to an exacerbation of COPD with persistent hypercapnia (PaCO2 >7 kPa) 2–4 weeks following resolution of the acute episode LTOT: no details	PaCO2 >7kPa	Pressure	Usual care	Adherence
Struik et al,^Citation32 the Netherlands	201 (83/201, 41%)	12 months	Posthospital: patients included after episode of acute respiratory failure LTOT: 77%	Yes (PaCO2 >6.0 kPa)	Pressure	Usual care	Survival, hospitalizations, exacerbations, QoL, adherence, FEV1, FVC, PaCO2, and PaO2
Xiang et al,^Citation33 People’s Republic of China	40 (31/40, 77%)	24 months	Posthospital: after discharge from hospital. All admitted with acute exacerbation and type II respiratory failure. Discharged once stable LTOT: 100%	Inclusion criterion: PaCO2 $55 mmHg (or 7.33 kPa)	Pressure	Usual care	Survival, hospitalizations, FEV1, FVC, PaCO2, PaO2, dyspnea, and 6MWD
Dreher et al,^Citation38 Germany Crossover RCT	17 (9/13a, 69%)	6 weeks	Stable. Patients enrolled during stable phase of disease. Excluded if weaned from invasive ventilation or intubated during the last 3 months LTOT: 100%	PaCO2 >45 mmHg (or 6.0 kPa)	Blood gases. High intensity: high pressure with respiratory rates beyond the spontaneous breathing frequency	Blood gases. Low intensity: low pressure and back-up respiratory rates of 8 bpm	QoL, adherence, FEV1, PaCO2, and 6MWD
Murphy et al,^Citation40 UK Crossover RCT	12 (8/12, 66.7%)	6 weeks	Stable (no details on length of time without exacerbations) LTOT: no details	PaCO2 >6.0 kPa	Pressure. High intensity: high pressure and high back-up rate (2 bpm)	Pressure. High intensity: high pressure and low back-up rate (6 bpm)	QoL, adherence, and PaCO2
Oscroft et al,^Citation39 UK Crossover RCT	25 (13/25, 52%)	8 weeks	Stable (no exacerbations in preceding 4 weeks; clinical stability confirmed during overnight assessment) LTOT: 67%	PaCO2 >7.5 kPa	Pressure. Volume assured: set to enable adjustment of inspiratory pressure up to 25 mmHg, the maximum possible with this ventilator	Pressure. Pressure preset: set at similar pressure settings that subject had previously used	QoL, adherence, FEV1, FVC, and PaCO2
Controlled studies: stable disease
Clini et al,^Citation28 Italy Prospective	49 (36/49, 73%)	Mean (SD) 35 (7) months	Stable clinical state, ie, stability in blood gas values and pH (>7.35), and lack of exacerbation in the preceding 4 weeks LTOT: 100%	Inclusion criterion: PaCO2 >6 kPa	Volume	Usual care	Survival, hospitalizations, adherence, FEV1, FVC, PaCO2, PaO2, and 6MWD
Clini et al,^Citation22 Italy Prospective	34 (21/34, 62%)	18 months	Stable: noninvasive mechanical ventilation was initiated during a preliminary hospital trial when patients were in a stable state LTOT: 100%	Inclusion criterion: PaCO2 >6.7 kPa	Volume	Usual care + “home supervision program”	Survival, hospitalizations, PaCO2, and PaO2
Paone et al,^Citation30 Italy Prospective	60 (31/60, 52%)	24 months	Stable. Patients enrolled 3 months after discharge from hospital (for exacerbation); free from exacerbations for at least 4 weeks LTOT: 100%	Yes (PaCO2 >50 mmHg) (6.6 kPa)	Volume	Usual care	Survival, hospital admissions, and blood and sputum inflammatory biomarkers
Tsolaki et al,^Citation29 Greece Prospective	49 (31/46a, 67%)	12 months	Stable clinical state, as assessed by a pH >7.35, and free from exacerbations at least 4 weeks preceding recruitment LTOT: proportion unclear	Inclusion criterion: PaCO2 >50 mmHg (6.6 kPa)	Pressure	Usual care	Survival, exacerbations, hospitalizations, QoL, adherence, PaCO2, and PaO2
Controlled studies: posthospitalization for acute exacerbation
Budweiser et al,^Citation36 Germany Prospective	140 (91/140, 65%)	NIV mean (SD) 19.8 (12.9) months and usual care 12.9 (9.9) months	Both stable and posthospital patients (classified as posthospital): patients with immediately preceding exacerbation eligible for inclusion (proportion of patients not stated) LTOT: 55% prior to study and 91% upon discharge	Inclusion criterion: PaCO2 $50 mmHg (or 6.6 kPa)	Blood gases	Usual care	Survival and adherence
Heinemann et al,^Citation35 Germany Retrospective	82 (59/82, 72%)	12 months	Posthospital: patients with severe COPD who required prolonged weaning from invasive mechanical ventilation due to acute exacerbation, pneumonia, or postoperative respiratory failure LTOT: proportion unclear	Inclusion criterion: PaCO2 >52.5 mmHg (or 6.9 kPa) for those receiving NIV	Blood gases	Usual care	Survival and adherence
Lu et al,^Citation34 People’s Republic of China Retrospective	44 (31/44, 70%)	6 months	Posthospital: patients who were discharged once they were stable following hospitalization LTOT: 100%	Inclusion criterion: PaCO2 $55 mmHg (or 7.33 kPa)	Blood gases	Usual care	Survival, hospitalizations adherence, FEV1, FVC, PaCO2, PaO2, and 6MWD
Milane and Jonquet,^Citation37 France Retrospective	66 (62/66, 94%)	Up to 10 years	Posthospital: patients hospitalized during 1973–1983 due to an exacerbation LTOT: no details	“Blood gas measurements determined eligibility for NIV”. Mean (SD) PaCO2 NIV group 56.1 (5.3) mmHg (or 7.45 kPa) and usual care group 48 (6.6) mmHg (or 6.4 kPa)	No details	Usual care	Survival
Controlled studies: no details on stable/posthospital
Laier-Groeneveld and Criee,^Citation56 Germany Retrospective	100 (no details on % male)	Up to 4 years	No details LTOT: no details	Hypercapnia a prerequisite for treatment with NIV (no cut-off stated)	Blood gases	Usual care	Survival
Pahnke et al,^Citation57 Germany Retrospective	40 (no details on % male)	Up to 8 years	No details LTOT: no details	No details	No details	Usual care	Survival and adherence

Notes: Not listed in table: patients across all studies were GOLD stage III and/or IV or were described as “severe” (where reported); 18 studies provided details on assessing patients for obstructive sleep apnea (to rule out overlap syndrome). Main outcomes in meta-analyses are given in bold.

a The number of male patients/number of completers.

b Based on those originally enrolled.

Abbreviations: LTOT, long-term oxygen therapy; NIV, noninvasive ventilation; PaCO₂, partial pressure of carbon dioxide; QoL, quality of life; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; PaO₂, partial pressure of oxygen; SD, standard deviation; 6MWD, 6-minute walk distance; RCT, randomized controlled trial; bpm, beats per minute.

Figure 1 PRISMA flow diagram (study selection process).

Abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs, randomized controlled trials; NIV, noninvasive ventilation.

Figure 2 Mortality (relative risk).

Notes: *Calculated by authors of this report. ⁺Controlled study with matching.

Abbreviations: RR, relative risk; CI, confidence interval; RCT, randomized controlled trial; NIV, noninvasive ventilation.

Figure 3 Hospital admissions per patient per year (weighted mean difference).

Notes: *Calculated by authors of this report. ^#Individual mean differences (95% CI) presented for this outcome.

Abbreviations: CI, confidence interval; WMD, weighted mean difference; RCTs, randomized controlled trials; ICU, intensive care unit; NIV, noninvasive ventilation.

Figure 4 PaO₂ (mean difference).

Notes: *Calculated by authors of this report. ^aMeasurement performed regardless of oxygen use. ^bMeasurements both on room air or both on oxygen at the same flow rate.

Abbreviations: PaO₂, partial pressure of oxygen; NIV, noninvasive ventilation; CI, confidence interval; NR, not reported.

Figure 5 PaCO₂ (mean difference).

Notes: *Calculated by authors of this report. ^aMeasurement performed regardless of oxygen use. ^bMeasurements both on room air or both on oxygen at the same flow rate.
Abbreviations: PaCO₂, partial pressure of carbon dioxide; NIV, noninvasive ventilation; CI, confidence interval.

Figure 6 Hypercapnia and clinical outcomes.

Notes: (A) Mortality (RR) and baseline PaCO₂. (B) Mortality (RR) and change in PaCO₂. (C) Hospital admissions (MD) and baseline PaCO₂. (D) Hospital admissions (MD) and change in PaCO₂.
Abbreviations: RR, relative risk; PaCO₂, partial pressure of carbon dioxide; MD, mean difference.

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