Long-term non-invasive ventilation in patients with chronic obstructive pulmonary disease (COPD): 2021 Canadian Thoracic Society Clinical Practice Guideline update

Figures & data

Table

PICO Question	Recommendations	Strength of Recommendation*	Certainty of Evidence
1a) Does long-term NIV, as compared to best practice without NIV in patients with stable severe COPD and chronic hypercapnic respiratory failure, result in improved:  1. Dyspnea  2. HRQoL  3. Daytime PaCO2  4. Hospitalization  5. Survival	In patients with stable severe COPD and chronic hypercapnic respiratory failure (PaCO2 ≥ 52 mmHg), we suggest long-term NIV to improve survival.	Weak/conditional	Low certainty
1b) Does long-term NIV, as compared to best practice without NIV in patients with COPD post hypercapnic exacerbation requiring NIV acutely, result in improved:  1. Dyspnea  2. HRQoL  3. Daytime PaCO2  4. Hospitalization  5. Survival	In patients with severe COPD on LTOT who remain significantly hypercapnic (persistent PaCO2 ≥ 52 mmHg) at least 2 weeks after discontinuing NIV for an acute exacerbation, we suggest long-term NIV to delay hospital readmission.	Weak/conditional	Very low certainty
2.  When applying long-term NIV to patients with COPD and chronic hypercapnic respiratory failure, does high-intensity NIV compared to low-intensity NIV improve:  1. Dyspnea  2. HRQoL  3. Daytime PaCO2	We suggest high-intensity NIV instead of low-intensity NIV to improve PaCO2 in patients with COPD and chronic hypercapnic respiratory failure (persistent PaCO2 ≥ 52 mmHg).	Weak/conditional	Low certainty
3.  When applying long-term NIV to patients with COPD, does volume-assured pressure-preset NIV compared to standard pressure-preset NIV improve:  1. Dyspnea  2. HRQoL  3. Daytime PaCO2	We do not recommend the use of volume-assured pressure-preset NIV over standard pressure-preset NIV in patients with COPD and chronic hypercapnic respiratory failure.	Strong	Low certainty

*Strength of recommendation is based on certainty of evidence, balance of desirable and undesirable effects, patient values, preferences, resource use, health equity, acceptability of an intervention and feasibility of implementation. Details are presented in the following Results section. LTOT: Long-term oxygen therapy.

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PICO 1a): Does long-term NIV, as compared to best practices without NIV in patients with stable severe COPD and chronic hypercapnic respiratory failure, result in improved: 1. Dyspnea 2. HRQoL 3. Daytime PaCO2 4. Hospitalization 5. Survival Recommendation: In patients with stable severe COPD and chronic hypercapnic respiratory failure (PaCO2 ≥ 52 mm Hg), we suggest long-term NIV to improve survival. (weak/conditional recommendation, low certainty evidence)

Table 1. Results for outcomes in studies of long-term NIV in patients with stable severe COPD.

Author/Year	Study Type	# of pts	OUTCOMES
			Dyspnea	HRQoL	PaCO2	Hospitalization	Mortality	Other outcomes
Strump et al.^31 1991	Randomized, cross-overNIV vs usual care	23	ND	N/A	ND	N/A	N/A	Certain neuropsychological measures improved. ND in lung function, exercise capacity, sleep; and depression
Meecham Jones et al. ^16 1995	Randomized, cross-over NIV + LTOT vs. LTOT alone	18	N/A	Improved SGRQ symptom scores	Improved	N/A	N/A	Improved total sleep time and efficiency, and nocturnal transcutaneous PaCO2. ND in lung function and exercise capacity.
Gay et al. ^34 1996	Randomized, parallel group NIV vs sham NIV	13	N/A	N/A	ND	N/A	N/A	ND in lung function, exercise capacity, sleep efficiency and nocturnal O2 saturation.
Casanova et al. ^3 2000	Randomized, parallel group NIV + LTOT vs LTOT alone	52	Reduced dyspnea (MRC and Borg)	N/A	ND	ND at 1 year	ND	ND in number and severity of acute exacerbations, lung function, ad = bd psychomotor coordination measures (except one).
Garrod et al. ^29 2000	Randomized parallel group, NIV + exercise vs exercise alone	45	ND in dyspnea part of CRQ	Improved CRQ with NIV	ND	N/A	N/A	Shuttle walk test improved. ND in lung function and sleep architecture.
Clini et al. ^4 2002	Randomized, parallel group NIV + LTOT vs LTOT alone	90	Reduced dyspnea (MRC)	Improved MRF-28. SGRQ: ND	ND	ND	ND	ND in lung function, exercise capacity and sleep quality.
McEvoy et al. ^6 2009	Randomized, parallel group NIV + LTOT vs LTOT alone	144	N/A	ND in SGRQ. Deterioration in several subscales of the SF-36 (poorer general and mental health) and POMS (Less vigor and more confusion and bewilderment).	ND	ND	Improved survival	Increased % REM sleep and reduced transcutaneous CO2 in sleep. ND in lung function.
Oscroft et al. ^33 2010	Randomized, parallel group withdrawal NIV vs usual care in patients who were previously on NIV	10	N/A	SGRQ deterioration with NIV withdrawal.	Improved with NIV	N/A	N/A	Nocturnal transcutaneous PaCO2 and daytime bicarbonate improved.
Duiverman et al. ^28 2011	Randomized, parallel group NIV + rehabilitation vs rehabilitation alone	56	MRC better with NIV	MRF improved. CRQ ND	PaCO2 improved	ND	N/A	FEV1, 6MWT, activity level and mood improved. ND in exacerbation rate.
Bhatt et al. ^27 2013	Randomized, parallel group NIV vs usual care	30	Improvement in TDI at 6 weeks and 3 months but only TDI-Task at 6 months.	CRQ only mastery domain improved	ND	N/A	N/A	Oxygen saturation improved. ND in lung function, 6MWD, Pittsburgh Sleep Quality index and exacerbations.
Kohnlein et al. ^5 2014	Randomized, parallel group NIV vs usual care	195	N/A	SF-36 General Health Perception subscale, SGRQ summary and SRI improved.	Improved with NIV	Unclear (rare)	Improved survival with NIV.	SaO2, FEV1, bicarbonate improved. ND in 6 MWD.
Márquez-Martín et al. ^30 2014	Randomized, parallel group NIV vs exercise vs NIV + exercise	45	mMRC ND	CRQ ND	Improved with NIV	N/A	N/A	ND in peripheral muscle strength, 6MWT, BODE and inflammatory biomarkers.
Zhou et al. ^32 2017	Randomized, parallel group NIV vs usual care	115	TDI ND	Trend to improve CAT. SRI ND.	Improved with NIV	N/A	N/A	More patients reaching the MCID on the 6MWT in the NIV group. ND in oxygenation, base excess and lung function. Built-in software could provide accurate monitoring of ventilator performance.

Abbreviations: NIV, non-invasive ventilation; COPD, chronic obstructive pulmonary disease; HRQoL, health-related quality of life; PaCO₂, partial pressure of carbon dioxide; N/A, Not Assessed; ND, no significant difference found in outcome between study groups; LTOT, long-term oxygen therapy; SGRQ, St. George’s Respiratory Questionnaire; mMRC, modified Medical Research Council; POMS, profile of mood states; REM, rapid eye movement; CRQ, Chronic Respiratory Questionnaire; MRF-28, Maugeri Foundation Respiratory Failure Questionnaire; SF-36, Short Form Health Survey; SRI, Severe Respiratory Insufficiency Questionnaire; FEV₁, forced expiratory volume in 1 s; 6MWT, 6-minute walking test; CAT, COPD assessment test; TDI, Transition Dyspnea Index; MCID, minimal clinically important difference.

Table 2. Inclusion criteria and NIV parameters in studies of long-term NIV in patients with stable severe COPD.

Author/Year	Required airflow obstruction	Reported baseline FEV1 (mean or median)	Required blood gases	Reported baseline PaCO2 (mean or median, in mm Hg)	Reported NIV pressures (mean or median, in cmH2O)
Strump et al. ^31 1991	FEV1 < 1 L	33% predicted	No pre-established criteria	49 (range 35-67)	IPAP = 15 EPAP = 2
Meecham Jones et al. ^16 1995	FEV1 < 50% predicted	0.86L	PaCO2 > 45 mmHg on LTOT	55.8	IPAP = 18 EPAP = 2
Gay et al. ^34 1996	FEV1 < 40% predicted	0.67L	PaCO2 > 45 mmHg	51.8	IPAP = 10 EPAP = 2
Casanova et al. ^3 2000	FEV1 < 45% predicted	30.1% predicted	No pre-established criteria	52.1	IPAP = 12 EPAP = 4
Garrod et al. ^29 2000	FEV 1 < 50% predicted	34% predicted	No pre-established criteria	45.1	IPAP: 16 (range 13–24) EPAP : 4 (range 4–6)
Clini et al. ^4 2002	FEV1 < 1.5 L	29.1% predicted	PaCO2 > 50 mmHg on LTOT	54.8	IPAP = 14 EPAP = 2
McEvoy et al. ^6 2009	FEV1 < 1.5 L or < 50% predicted	24.1% predicted	PaCO2 > 46 mmHg on LTOT	53.5	IPAP = 12.9 EPAP = 5.1
Oscroft et al. ^33 2010	FEV1 < 50% predicted	0.84L	PaCO2 > 56 mmHg	63.8 (historical prior to NIV start)	IPAP = 30 EPAP = 4
Duiverman et al. ^28 2011	FEV1 < 50% predicted	0.84 L	PaCO2 > 45 mmHg	52 (approx.)	IPAP = 23 EPAP = 6
Bhatt et al. ^27 2013	FEV1 < 50% predicted	30.2 % predicted	PaCO2 < 52 mmHg		IPAP = 15 EPAP = 5
Kohnlein et al. ^5 2014	FEV1 < 30% predicted	26.5% predicted	PaCO2 > 51.9 mmHg	58.5	IPAP = 21.6 EPAP = 4.8
Márquez-Martín et al. ^30 2014	FEV1 <50% predicted	34% predicted	PaCO2 > 45 mmHg PaO2 < 60 mmHg	50	IPAP = 16 EPAP = 4
Zhou et al. ^32 2017	FEV1 < 50% predicted	25.7% predicted	Hypercapnia without further precision. on LTOT	58	IPAP = 17.8 EPAP = 4.2

Abbreviations: NIV, non-invasive ventilation; COPD, chronic obstructive pulmonary disease; FEV₁, Forced expiratory volume in 1 s; PaCO₂, partial pressure of carbon dioxide in arterial blood; cmH₂O, centimeters of water column; LTOT, long-term oxygen therapy; IPAP, inspiratory positive airway pressure; EPAP, expiratory positive airway pressure.

Table

PICO 1b): Does long-term NIV, as compared to best practice without NIV in patients with COPD, post hypercapnic exacerbation requiring NIV acutely, result in improved: 1. Dyspnea 2. HRQoL 3. Daytime PaCO2 4. Hospitalization 5. Survival Recommendation: In patients with severe COPD on LTOT who remain significantly hypercapnic (persistent PaCO2 > 52 mmHg) for at least 2 weeks after discontinuing NIV for an acute exacerbation, we suggest long-term NIV to delay hospital readmission. (weak/conditional recommendation, very low certainty evidence)

Table 3. Results for outcomes in studies of long-term NIV in patients with COPD post-acute severe hypercapnic exacerbation.

Author/Year	Study Type	# pts	OUTCOMES
			Dyspnea	HRQoL	PaCO2	Hospitalization	Mortality	Other outcomes
Cheung et al. ^8 2010	Randomized parallel group NIV vs CPAP	49	N/A	N/A	ND	ND	ND	Reduction in the composite outcome: recurrent severe hypercapnic COPD exacerbation with repeat or increased NIV, intubation or death. ND in median time to readmission, and severe adverse events.
De Backer et al. ^40 2011	Randomized parallel group NIV vs usual care	15	N/A	N/A	Improved in NIV group only but no between- treatment comparison	N/A	N/A	Increased 6-MWD in NIV group (no between-group comparison). More inhomogeneous redistribution of mass flow (to better perfused areas). ND in lung function.
Struik et al. ^41 2014	Randomized parallel group NIV + vs usual care	201	MRC: ND	ND in CRQ, MRF-28, CRQ, SRI. Trend for improved SRI.	Improved slightly more in NIV group; ND when only comparing measurements done under same FiO2 conditions at baseline and follow-up	ND	ND	Reduced mean nocturnal PtcCO2. ND in number of exacerbations at home, mood, daily activities and lung function.
Murphy et al. ^7 2017	Randomized parallel group NIV LTOT vs LTOT alone	116	MRC dyspnea scale (not reported)	Improved SGRQ score at 3 months but not thereafter. ND in SRI.	Improved at 3 months but not thereafter	Reduction in the composite outcome of time to readmission or death. Reduced 28-day readmissions in post-hoc analysis	ND	Reduction in the composite outcome of time to readmission or death. Reduced COPD exacerbation rate.

Abbreviations: NIV, non-invasive ventilation; COPD, chronic obstructive pulmonary disease; PaCO₂, partial pressure of carbon dioxide in arterial blood; cmH₂O, centimeters of water column; N/A, Not Assessed; ND, no difference found in outcome between treatments; NIV, non-invasive ventilation; CPAP, continuous positive airway pressure; LTOT, long-term oxygen therapy; SGRQ, St. George’s Respiratory Questionnaire; MRC, Medical Research Council; CRQ, Chronic Respiratory Questionnaire; MRF-28, Maugeri Foundation Respiratory Failure Questionnaire; SF-36, Short Form Health Survey; SRI, Severe Respiratory Insufficiency Questionnaire; CAT, COPD assessment test; 6MWD, 6-minute walking distance.

Table 4. Inclusion criteria and NIV parameters in studies of long-term NIV in patients with COPD post-acute severe hypercapnic exacerbation.

Author/Year	Required airflow obstruction	Reported baseline FEV1 (mean or median)	Required blood gases	Reported baseline PaCO2 (mean or median, in mmHg)	Reported NIV pressures (mean or median, in cmH2O)
Cheung et al. ^8 2010	COPD (no FEV1 criteria)	29.7% predicted	No specified criteria 48 hours following an episode of AHRF	56.2	IPAP = 14.8 EPAP = 5
De Backer et al. ^40 2011	FEV1 < 50% predicted	29.8% predicted	PaCO2 > 45 mmHg Day 5–12 after an episode of AHRF	54.4	N/A
Struik et al. ^41 2014	FEV1 < 50% predicted	26% predicted	PaCO2 > 45 mmHg 48 hours after an episode of AHRF	58.5	IPAP = 19 EPAP = 4
Murphy et al. ^7 2017	FEV1 < 50% predicted	23.4% predicted	PaCO2 > 53 mmHg and hypoxemia (criteria for LTOT) 2- 4 weeks after an episode of AHRF	59	IPAP = 24 EPAP = 4

Abbreviations: NIV, non-invasive ventilation; COPD, chronic obstructive pulmonary disease; PaCO₂, partial pressure of carbon dioxide in arterial blood; cmH₂O, centimeters of water column; AHRF, acute hypercapnic respiratory failure; FEV₁, forced expiratory volume in 1 s; LTOT, long-term oxygen therapy; IPAP, inspiratory positive airway pressure; EPAP, expiratory positive airway pressure.

Table

PICO 2: When applying long-term NIV to patients with COPD and chronic hypercapnic respiratory failure, does high-intensity NIV compared to low-intensity NIV improve: 1. Dyspnea 2. HRQoL 3. Daytime PaCO2 Recommendation: We suggest high-intensity non-invasive ventilation instead of low-intensity non-invasive ventilation to improve PaCO2 in patients with COPD and chronic hypercapnic respiratory failure (persistent PaCO2 > 52 mmHg). (weak/conditional recommendation, low certainty evidence)

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PICO 3: When applying long-term NIV to patients with COPD, does volume-assured pressure-preset NIV compared to standard pressure-preset NIV improve: 1. Dyspnea 2. HRQoL 3. Daytime PaCO2 Recommendation: We do not recommend the use of volume-assured pressure-preset NIV over standard pressure-preset NIV in patients with COPD and chronic hypercapnic respiratory failure. (strong recommendation, low certainty evidence)

Table

Criteria	Inclusion	Exclusion
Study Type	Randomized control trials	Systematic reviews Meta-analysis Cohort studies commentaries, editorials, case control studies Letters to the editor that do not provide primary source data. Conference abstracts. Not English
Age	Adult >18 years of age	< 18 years of age
Population	PICO 1 a) Patients with COPD with severe COPD and chronic hypercapnic respiratory failure who are otherwise stablePICO 1 b) Patients with COPD and chronic hypercapnic respiratory failure who are recovering from a recent hospitalization for acute-on-chronic hypercapnic respiratory failure PICO 2 and 3 Patients with COPD and chronic hypercapnic respiratory failure	without chronic hypercapnic respiratory failure
Intervention	Long-term NIV, high-intensity NIV, low-intensity NIV, volume-assured pressure-preset NIV, home NIV	intervention is other than what is described in the inclusion criteria
Comparator	PICO 1 a) b) long-term NIV as compared to best practices without NIV PICO 2 high-intensity NIV compared to low-intensity NIV PICO 3 volume-assured pressure-preset NIV compared to standard pressure-preset NIV	comparator is other than what is described in the inclusion criteria
Outcomes	Dyspnea, Blood gases, Health Related Quality of Life, Hospitalization, Survival,	Outcome is other than what is described in the inclusion criteria

Abbreviations: PICO, Patient/problem, Intervention, Comparison, Outcome; COPD, chronic obstructive pulmonary disease; NIV, non-invasive ventilation.

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