Home noninvasive ventilation in severe COPD: in whom does it work and how?

Background: Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide (PaCO2), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved PaCO2. Methods: We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on PaCO2, HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in PaCO2. Findings: Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH2O) and with lower adherence (<5 versus ≥5 h·day-1) had less improvement in PaCO2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. PaCO2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in PaCO2. Interpretation: With greater pressure support and better daily NIV usage, a larger improvement in PaCO2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal PaCO2.

Chronic non-invasive ventilation for chronic obstructive pulmonary disease.

BACKGROUND: Chronic non-invasive ventilation (NIV) is increasingly being used to treat people with COPD who have respiratory failure, but the evidence supporting this treatment has been conflicting. OBJECTIVES: To assess the effects of chronic non-invasive ventilation at home via a facial mask in people with COPD, using a pooled analysis of IPD and meta-analysis. SEARCH METHODS: We searched the Cochrane Airways Register of Trials, MEDLINE, Embase, PsycINFO, CINAHL, AMED, proceedings of respiratory conferences, clinical trial registries and bibliographies of relevant studies. We conducted the latest search on 21 December 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing chronic NIV for at least five hours per night for three consecutive weeks or more (in addition to standard care) versus standard care alone, in people with COPD. Studies investigating people initiated on NIV in a stable phase and studies investigating NIV commenced after a severe COPD exacerbation were eligible, but we reported and analysed them separately. The primary outcomes were arterial blood gases, health-related quality of life (HRQL), exercise capacity (stable COPD) and admission-free survival (post-exacerbation COPD). Secondary outcomes for both populations were: lung function, COPD exacerbations and admissions, and all-cause mortality. For stable COPD, we also reported respiratory muscle strength, dyspnoea and sleep efficiency. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. After inclusion of a study, we requested the IPD. We analysed continuous and time-to-event data using linear- and cox-regression mixed-effect models with a random effect on study level. We analysed dichotomous IPD using generalised estimating equations. We adjusted all models for age and sex. We assessed changes in outcomes after three and 12 months.  We also conducted a meta-analysis on aggregated trial data. MAIN RESULTS: We included 14 new RCTs in this review update, in addition to the seven previously included. Seventeen studies investigated chronic NIV in stable COPD and four studies investigated chronic NIV commenced after a severe COPD exacerbation. Three studies compared NIV to sham continuous positive airway pressure (2 to 4 cmH2O). Seven studies used a nasal mask, one study used an oronasal mask and eight studies used both interfaces. Five studies did not report the interface. The majority of trials (20/21) were at high risk of performance bias due to an unblinded design. We considered 11 studies to have a low risk of selection bias and 13 to have a low risk of attrition bias. We collected and analysed the IPD from 13 stable COPD studies (n = 778, 68% of the participants included) and from three post-exacerbation studies (n = 364, 96% of the participants included). In the stable COPD group, NIV probably results in a minor benefit on the arterial partial pressure of oxygen (PaO2) after three months (adjusted mean difference (AMD) 0.27 kPa, 95% CI 0.04 to 0.49; 9 studies, 271 participants; moderate-certainty evidence), but there was little to no benefit at 12 months (AMD 0.09 kPa, 95% CI -0.23 to 0.42; 3 studies, 171 participants; low-certainty evidence). The arterial partial pressure of carbon dioxide (PaCO2) was reduced in participants allocated to NIV after three months (AMD -0.61 kPa, 95% CI -0.77 to -0.45; 11 studies, 475 participants; high-certainty evidence) and persisted up to 12 months (AMD -0.42 kPa, 95% CI -0.68 to -0.16; 4 studies, 232 participants; high-certainty evidence).  Exercise capacity was measured with the 6-minute walking distance (minimal clinical important difference: 26 m). There was no clinically relevant effect of NIV on exercise capacity (3 months: AMD 15.5 m, 95% CI -0.8 to 31.7; 8 studies, 330 participants; low-certainty evidence; 12 months: AMD 26.4 m, 95% CI -7.6 to 60.5; 3 studies, 134 participants; very low-certainty evidence). HRQL was measured with the Severe Respiratory Insufficiency and the St. Georges's Respiratory Questionnaire and may be improved by NIV, but only after three months (3 months: standardised mean difference (SMD) 0.39, 95% CI 0.15 to 0.62; 5 studies, 259 participants; very low-certainty evidence; 12 months: SMD 0.15, 95% CI -0.13 to 0.43; 4 studies, 200 participants; very low-certainty evidence). Lastly, the risk for all-cause mortality is likely reduced by NIV (adjusted hazard ratio (AHR) 0.75, 95% CI 0.58 to 0.97; 3 studies, 405 participants; moderate-certainty evidence). In the post-exacerbation COPD group, there was little to no benefit on the PaO2 after three months, but there may be a slight decrease after 12 months (3 months: AMD -0.10 kPa, 95% CI -0.65 to 0.45; 3 studies, 234 participants; low-certainty evidence; 12 months: -0.27 kPa, 95% CI -0.86 to 0.32, 3 studies; 170 participants; low-certainty evidence). The PaCO2 was reduced by NIV at both three months (AMD -0.40 kPa, 95% CI -0.70 to -0.09; 3 studies, 241 participants; moderate-certainty evidence) and 12 months (AMD -0.52 kPa, 95% CI -0.87 to -0.18; 3 studies, 175 participants; high-certainty evidence). NIV may have little to no benefit on HRQL (3 months: SMD 0.25, 95% CI -0.01 to 0.51; 2 studies, 219 participants; very low-certainty evidence; 12 months: SMD 0.25, 95% -0.06 to 0.55; 2 studies, 164 participants; very low-certainty evidence). Admission-free survival seems improved with NIV (AHR 0.71, 95% CI 0.54 to 0.94; 2 studies, 317 participants; low-certainty evidence), but the risk for all-cause mortality does not seem to improve (AHR 0.97, 95% CI 0.74 to 1.28; 2 studies, 317 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Regardless of the timing of initiation, chronic NIV improves daytime hypercapnia. In addition, in stable COPD, survival seems to be improved and there might be a short term HRQL benefit. In people with persistent hypercapnia after a COPD exacerbation, chronic NIV might prolong admission-free survival without a beneficial effect on HRQL. In stable COPD, future RCTs comparing NIV to a control group receiving standard care might no longer be warranted, but research should focus on identifying participant characteristics that would define treatment success. Furthermore, the optimal timing for initiation of NIV after a severe COPD exacerbation is still unknown.

Improvement in hypercapnia does not predict survival in COPD patients on chronic noninvasive ventilation.

PURPOSE: It has recently been shown that chronic noninvasive ventilation (NIV) improves a number of outcomes including survival, in patients with stable hypercapnic COPD. However, the mechanisms responsible for these improved outcomes are still unknown. The aim of the present study was to identify parameters associated with: 1) an improved arterial partial pressure of carbon dioxide (PaCO2) and 2) survival, in a cohort of hypercapnic COPD patients treated with chronic NIV. PATIENTS AND METHODS: Data from 240 COPD patients treated with chronic NIV were analyzed. Predictors for the change in PaCO2 and survival were investigated using multivariate linear and Cox regression models, respectively. RESULTS: A higher level of bicarbonate before NIV initiation, the use of higher inspiratory ventilator pressures, the presence of anxiety symptoms, and NIV initiated following an exacerbation compared to NIV initiated in stable disease were associated with a larger reduction in PaCO2. A higher body mass index, a higher FEV1, a lower bicarbonate before NIV initiation, and younger age and NIV initiation in stable condition were independently associated with better survival. The change in PaCO2 was not associated with survival, neither in a subgroup of patients with a PaCO2 >7.0 kPa before the initiation of NIV. CONCLUSION: Patients with anxiety symptoms and a high bicarbonate level at NIV initiation are potentially good responders in terms of an improvement in hypercapnia. Also, higher inspiratory ventilator pressures are associated with a larger reduction in PaCO2. However, the improvement in hypercapnia does not seem to be associated with an improved survival and emphasizes the need to look beyond PaCO2 when considering NIV initiation.

The Severe Respiratory Insufficiency Questionnaire scored best in the assessment of health-related quality of life in chronic obstructive pulmonary disease.

OBJECTIVE: There are limited data on health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure during an admission requiring ventilatory support. The aim was to assess and compare the reliability and validity of the Clinical COPD Questionnaire (CCQ), Chronic Respiratory Questionnaire (CRQ), Maugeri Respiratory Failure-28 (MRF-28) Questionnaire, and Severe Respiratory Insufficiency (SRI) Questionnaire in patients with very severe COPD. STUDY DESIGN AND SETTING: One hundred eighty hospitalized patients filled out the CCQ, CRQ, MRF-28, SRI, Groningen Activity Restriction Scale (GARS), Hospital Anxiety and Depression Scale (HADS), and the Medical Research Council Dyspnea Scale (MRC). Reliability was examined by assessing distribution of total scores, floor and ceiling effects, and internal consistency (using Cronbach α coefficient). Construct validity between questionnaires and also the other measurements were tested with Spearman ρ. RESULTS: All four questionnaires were feasible in this setting and had reasonable characteristics for distribution of total scores, floor and ceiling effects, internal consistency, and construct validity. On balance, the SRI scored best. Additionally, the SRI had a remarkable high explained variance by HADS, GARS, and MRC (73%). CONCLUSION: The SRI performed slightly better than the CCQ, CRQ, and MRF-28, which renders it the preferred questionnaire for scoring HRQL in patients with very severe COPD.

Nocturnal non-invasive positive pressure ventilation for stable chronic obstructive pulmonary disease.

BACKGROUND: Non-invasive positive pressure ventilation (NIPPV) is effective in treating acute exacerbations of chronic obstructive pulmonary disease (COPD). Nocturnal non-invasive positive pressure ventilation (nocturnal-NIPPV) has been proposed as an intervention for stable hypercapnic patients with COPD. OBJECTIVES: To assess the effects of nocturnal-NIPPV at home via nasal mask or face mask in people with COPD by using a meta-analysis based on individual patient data (IPD). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register. We performed the latest search in August 2012. SELECTION CRITERIA: Randomised controlled trials in people with stable COPD that compared nocturnal-NIPPV at home for at least five hours per night, for at least three consecutive weeks plus standard therapy with standard therapy alone. DATA COLLECTION AND ANALYSIS: IPD were collected and two review authors assessed risk of bias independently. MAIN RESULTS: This update of the systematic review on nocturnal-NIPPV in COPD (Wijkstra 2002), has led to the inclusion of three new studies, leading to seven included studies on 245 people. We obtained IPD for all participants in all included studies. The 95% confidence interval (CI) of all outcomes included zero. These included partial pressure of CO2 and O2 in arterial blood, six-minute walking distance (6MWD), health-related quality of life (HRQoL), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (PImax) and sleep efficiency. The mean effect on 6MWD was small at 27.7 m and not statistically significant. Given the width of the 95% CI (-28.1 to 66.3 m), the real effect of NIPPV on 6MWD is uncertain and we cannot exclude an effect that is clinically significant (considering that the minimal clinically difference on 6MWD is around 26 m). AUTHORS' CONCLUSIONS: Nocturnal-NIPPV at home for at least three months in hypercapnic patients with stable COPD had no consistent clinically or statistically significant effect on gas exchange, exercise tolerance, HRQoL, lung function, respiratory muscle strength or sleep efficiency. Meta-analysis of the two new long-term studies did not show significant improvements in blood gases, HRQoL or lung function after 12 months of NIPPV. However, the small sample sizes of these studies preclude a definite conclusion regarding the effects of NIPPV in COPD.

Volume-targeted versus pressure-targeted noninvasive ventilation in patients with chest-wall deformity: a pilot study.

BACKGROUND: Long-term noninvasive ventilation (NIV) is an effective treatment for patients with chronic respiratory failure due to chest-wall deformity, but it is unknown if the time required for the patient to adjust to long-term NIV depends on whether the NIV is volume-targeted or pressure-targeted. OBJECTIVE: To determine whether volume controlled or pressure controlled NIV is easier to implement in patients with chronic respiratory failure due to chest-wall deformity. METHODS: We randomized 16 ventilator-naïve patients to receive either volume-targeted or pressure-targeted nocturnal NIV. The primary outcome was the number of days needed to successfully establish NIV, defined as adequate adjustment and effective ventilation, as measured with overnight arterial blood gas measurement. RESULTS: Two patients did not tolerate volume NIV, and switched to pressure NIV. NIV was successfully established in both groups after a median 6.0 days. There were no significant differences between the groups at any time point in P(aCO(2)) or P(aO(2)) improvement, nor in changes over time. CONCLUSIONS: There was no significant difference in days needed to successfully establish volume NIV versus pressure NIV in patients with chest-wall deformity. However, two patients switched successfully from volume NIV to pressure NIV, which suggests that they preferred pressure NIV.