Promoting Acceptance and Adherence to Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

OBJECTIVE: People with chronic obstructive pulmonary disease (COPD) may suffer from anxiety, depression, low quality of life, and cognitive deficits that could play a role in their clinical conditions. These situations could be worsened during the adaptation process to a new treatment such as noninvasive ventilation (NIV), which is often rejected or inappropriately used. The study aimed to analyze the impact of a brief psychological support intervention on adherence to NIV among patients with COPD.
METHODS: A two-branch randomized controlled trial was conducted on 90 patients with COPD who had an indication for NIV. The experimental group received cognitive behavioral therapy support, including counseling, relaxation, and mindfulness-based exercises. Controls received standard care and watched educational videos. The course had been structured for four to eight meetings at the hospital, at home, and/or via telemedicine.
RESULTS: The psychological intervention was related to improvements in both adherence to NIV (F(304) = 19.054, p < .001) and quality of life (F(156) = 10.264, p = .002) after eight meetings from baseline compared with the control group. Results indicated a significant change in the quality of life also over time (F(71.480) = 8.114, p = .006).
CONCLUSIONS: The findings suggest that the psychological intervention is an appropriate treatment for acceptance of and adherence to NIV in COPD in clinical practice and highlight the importance of determining the underlying reasons for NIV use.Trial Registration:ClinicalTrials.gov identifier NCT02499653.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world (1), and it is predicted to be the third by 2030 (2,3). According to the Global Burden of Disease Study, COPD was prevalent in more than 300 million people in 2013 (4). The prevalence of COPD in Europe ranges from about 15% to 20%, and it is higher in men than in women (5,6). Moreover, the disease burden and its impact are predicted to increase because of population aging (7–9).

COPD is characterized by an irreversible obstruction of the airways, which is associated with a progressive inflammation of the lung tissue together with an increased respiratory limitation, punctuated by recurrent episodes of exacerbations (10). Although diagnosed, thanks to spirometry, COPD is recognized as being more than a pulmonary disease. Comorbidities and extrapulmonary aspects such as cardiovascular disease, anemia, decreased muscle mass, diabetes, metabolic syndrome, dysfunctional skeletal myopathies, and osteoporosis are common in COPD people (11,12). Furthermore, psychological problems such as anxiety, depression (13), and cognitive impairment, overall or in specific domains like memory, executive functions, and cognitive flexibility (14), can contribute to complicating the clinical frame. Comorbidities and exacerbations can impair the quality of life (QoL) during the early stage of the illness, increasing mortality in the end stage, the burden of COPD management, and the healthcare costs (15). Anxiety and depression are common psychological comorbidities, which aggravate the clinical situation (16). Psychological aspects, including emotions and expectations (17), could interact with the physical symptoms. A clear example of the role of psychological factors in clinical management is provided by acceptance and adherence to noninvasive ventilation (NIV). NIV refers to the delivery of positive pressure ventilation through a noninvasive interface (e.g., nasal mask, face mask, or nasal plugs), rather than an invasive interface (endotracheal tube, tracheostomy), or postextubating respiratory failure. It can be used as ventilatory support for patients with acute or chronic respiratory failure. NIV works by creating a positive airway pressure—the pressure outside the lungs being greater than the pressure inside of the lungs. This causes air to be forced into the lungs (down the pressure gradient), lessening the respiratory effort and reducing the work of breathing. The number of days of NIV and hours of daily use differs, depending on the severity and course of the respiratory failure and the timing of application. For patients with chronic stable hypercapnic COPD, the use of nocturnal NIV in addition to usual care is recommended (18,19). The major sources of complications in the NIV’s usage are represented by pressure ulcers/necrosis (nasal bridge); facial or ocular abrasions; claustrophobia; anxiety; agitation; air swallowing with gastric/abdominal distension, potentially leading to vomiting and aspiration; hypotension if hypovolemic; aspiration; oronasal mucosal dryness; raised intracranial pressure; increased intraocular pressure; impaired communication; impaired nutrition; and noise and transport, which may also potentially increase patient discomfort (18–20). When properly used, NIV provides significant benefits in clinical outcomes, improving QoL and life expectancy and reducing hospital admissions and length of stay (21,22). Although NIV can produce a significant clinical improvement in COPD people, they often reject it or use it incorrectly, resulting in worse clinical outcomes and healthcare costs. Indeed, patients approaching its use, especially in the long term, face some complications, such as facial injuries due to the pressure exerted by the mask. Many, especially when using NIV for the first time, find it a stressful experience, eliciting emotions such as fear, anxiety, and panic attacks along with feelings of suffocation and claustrophobia, which can undermine acceptance and adherence to treatment if not result in outright rejection (23,24). Moreover, dyspnea during NIV is a complex problem: NIV aims to correct gaseous exchanges, but if it fails to relieve dyspnea—or worse, if dyspnea worsens during NIV—the combination of a life-threatening threat with a feeling of suffocation and thus lack of control leads to an aggravation of both dyspnea and anxiety, creating a traumatic vicious cycle (25,26). Previous studies suggested that the misuse or rejection of medication or NIV can be influenced by some psychological factors such as anxiety, depression, health beliefs, and cognitive impairment (27–29); the unacknowledged recognition of the illness; and the use of different devices and medications due to comorbidities (30–32). On the other hand, it is also important to note that NIV requires some lifestyle and behavioral changes during their routine care, which may affect adherence to the treatment (30). Nevertheless, only a few studies have paid attention to adherence to NIV in COPD people, and most of them have focused only on early NIV failure (33,34) or on the quantification of adherence (35). Moreover, most of the previous studies suggested that the difficult adjustment of the ventilator settings and the influence of NIV on sleep quality with spillover effects on daytime life can have an impact on its usage (36,37). Finally, COPD people who proved a lower survival benefit from the NIV usage exhibit worse average daily NIV adherence, because of the imbalance between the restrains that the device imposes and the improvement that they perceive in their clinical condition (37).

Psychosocial interventions have been suggested to be optimal both as alternative and complementary strategies to reduce physical impairments and psychological distress as well as to promote behavior change (38–40). This approach is supported by recent meta-analyses of controlled studies that emphasize that psychosocial interventions, especially those incorporating cognitive elements, reduce psychological distress (41) and, when based on meditative and relaxation practices, have the potential to improve physical and psychological outcomes (42).

Cognitive behavioral therapy (CBT) is a nonpharmacological, multicomponent therapy that aims to reduce and modify the psychological, behavioral, and physiological processes. It emphasizes helping individuals learn to be their therapists. Through exercises in the session and “homework” exercises outside of sessions, patients are helped to develop coping skills, whereby they can learn to change their thinking, problematic emotions, and behavior. In this way, the psychologist and patient work together, collaboratively, to develop an understanding of the problem and to develop a treatment strategy. Because of its scalability and increased recommendation in the management of COPD, CBT is particularly well positioned for promoting acceptance and adherence to NIV by targeting psychological factors such as anxiety, depression, representation of the disease, representation of the proposed therapies, therapeutic compliance, self-esteem, and cognitive functions as risks factors that could make the adaptation process difficult (43).

Objectives

The study aims to evaluate the impact of a short-term CBT intervention on NIV acceptance and adherence. Changes in QoL were considered as a secondary outcome. Moreover, another secondary outcome consisted of the identification of both psychological (anxiety, depression, representation of the disease, representation of the proposed therapies, therapeutic compliance, self-esteem, cognitive functions) and clinical factors (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], FEV1/FVC, the potential of hydrogen, partial arterial oxygen pressure, partial carbon dioxide pressure, hydrogen carbonate, fatigue, activities of daily living and instrumental activities of daily living, survival rates) that predicted NIV rejection or misuse.

METHODS

Ethical Considerations

The Ethics Committee of the IRCCS Fondazione Don Carlo Gnocchi (reference: February 15, 2015) and the Ethics Committee of Università Cattolica del Sacro Cuore (reference: January 21, 2016) in Milan (Italy) approved this study.

All participants provided written, informed consent before taking part in the study, and a psychologist explained the information contained in the Information Sheets and the Consent Form.

Study Design

The study was a randomized controlled trial, composed of two arms (experimental and control groups, both involving 4–8 weekly sessions) and four assessments (2 × 4 design) at baseline and at 3, 6, and 12 months after recruitment. The study was registered in the ClinicalTrials.gov repository (ID NCT02499653), and the details of the protocol were previously published (44).

Randomization

Sequence Generation

Participants were randomly allocated to the study groups (sequence generated by the Web site www.random.org) to ensure the internal validity of the results.

Allocation Concealment and Implementation

Allocation concealment was ensured as the automated randomization system did not release the code until the patient had been recruited into the trial, which took place after the completion of the baseline.

Blinding (Masking)

Individuals willing to participate in the trial did not know their assigned group in advance, nor did they know that the experimental and control groups received different treatments.

A debriefing was provided by the psychologist who conducted the intervention, addressing all possible questions. Moreover, a report of the study’s findings was sent to the participants.

The psychologist who led the intervention was blind to the assessment and vice versa. The research assistants involved in the assessments were instructed not to ask patients about their intervention content.

Participants and Setting

This study was conducted in a clinical research center (Respiratory Rehabilitation Unit, IRCCS Santa Maria Nascente, Fondazione Don Carlo Gnocchi, in Milan, Italy).

Inclusion and Exclusion Criteria

Eligible participants were aged at least 18 years, and they were inpatient or outpatient with moderate (Global Initiative for Obstructive Lung Disease 2%–50% ≤ FEV1 < 80% predicted) to severe (Global Initiative for Obstructive Lung Disease 3%–30% ≤ FEV1 < 50% predicted) COPD and were being newly introduced to NIV use at the time of the study.

Participants were excluded if they had an oncological history, were pregnant, or had an immunosuppressive disease as the main condition or a history of psychiatric disorders, except for anxiety and depression, as indicated in the clinical records.

Sample Size

According to preventive inherent power and sample size, the study required between 128 (statistical power of 0.80; α = .05; 1 − β =0.80; t(126) = 1.97) and 172 participants (statistical power equal to 0.90, α = 0.05; 1 − β =0.90; t(179) = 1.97) to detect a two-tailed difference. These statistical analyses were conducted taking into account data from scientific research with comparable primary outcome (45). We aimed to recruit up to 150 patients with COPD to account for a 15% dropout rate.

Time and Duration of the Study

This study was conducted between July 30, 2015, and December 31, 2018. After the pulmonary clinical visit, participants who met the inclusion criteria were invited to join the study. If they agreed, they provided written consent and were given a copy of the consent form along with an information sheet. Later, they underwent a psychological assessment (baseline [T0]). Follow-ups were planned at 3 (time 1 [T1]), 6 (time 2 [T2]), and 12 months (time 3 [T3]) from the recruitment date. Each medical assessment lasted 30 minutes, whereas the psychological one took about 45–50 minutes.

Instruments

The evaluation process was characterized by the investigation of the following five areas.

The medical and clinical assessment was performed during baseline, 3, 6, and 12 months from the recruitment (T0, T1, T2, and T3, respectively) and planned to collect data inherent to the primary outcome, acceptance, and adherence to NIV use, detected in terms of prescribed and effective hours and their difference as recorded by the ventilator. This part of the data collection also included examinations in terms of respiratory functions: spirometry (FEV1, FVC, FEV1/FVC); hemogasanalysis (arterial blood gases: potential of hydrogen, partial arterial oxygen pressure, partial carbon dioxide pressure2, hydrogen carbonate). Moreover, the Fatigue Severity Scale was used to assess fatigue (46); activities of daily living and instrumental activities of daily living were used to assess basic self-care tasks (47).

QoL was assessed using the EuroQoL. Three layers, referring to the Italian valuation set, were used to derive utility from the scores (48–53).

Sociodemographic information (age, sex, level of education, weight, height, body mass index, current profession (or previous, if retired), cohabitation, smoking habits, alcohol consumption, current and/or previous level of physical activity, drug therapies, use of psychotropic drugs, years of respiratory illness, the number of comorbidities and hospital admissions during the last year) were gathered at the first assessment (T0).

Psychological assessment was conducted during all the times of the study (T0, T1, T2, and T3, respectively) and consisted of measuring anxiety and depression, using the Hospital Anxiety and Depression Scale (HADS) (54), a 14-item scale; representation of the disease, assessed using the Brief Illness Perception Questionnaire (55), which is an application of the self-regulation theory; the therapeutic compliance, measured using the Questionnaire on Adhesion to Pharmacological and Dietetic Therapy (56); and self-esteem, measured using The Rosenberg Self-esteem Scale (57).

Cognitive functions were assessed using the Addenbrooke’s Cognitive Examination—Revised (ACE-R) (58), the Mini-Mental State Examination (MMSE) scale (59), and the Confusion Assessment Method (CAM), which was chosen to detect delirium (60).

Interventions

Cognitive and Behavioral Therapy

Participants assigned to the experimental group received a CBT intervention during the NIV adaptation process along with standard care. CBT protocol provides a flexible, patient-centered approach to increase patient engagement and adherence while addressing both the mental and physical health needs of patients with COPD who are faced with a new device—the NIV. Patients were guided through the initial receipt of modules focused on increasing awareness and control of physical and emotional symptoms and, subsequently, were supported on skill improvement based on the most pressing needs concerning adaptation. In particular, CBT components included counseling and psychological support, mindfulness-based cognitive restructuring exercises, and relaxation training (61). The intervention also included neuropsychological rehabilitation exercises, if required; this was decided on a case-by-case basis, thanks to the clinical notes and the ACE-R (58) and CAM’s administrations (60). The intervention was delivered by a licensed psychologist, trained in COPD management. The weekly sessions comprised three phases. First of all, each patient’s psychological needs were assessed at the beginning of the psychological intervention, paying special attention to aspects related to the disease (e.g., perception, understanding, awareness of symptoms) (62). Second, a lesson/brief presentation of the intervention components was conducted. The possible intervention components were as follows: information on the disease and its management to facilitate the understanding of how to cope with COPD; providing a supportive environment to address anxieties, doubts, and fears arising from the NIV idea; cognitive reframing exercises; lowering emotional arousal; and cognitive and behavioral coping strategies. Third, specific exercises related to each component were practiced (Figure 1).

FIGURE 1

Characteristics of the intervention sessions. CBT = cognitive behavioral therapy; COPD = chronic obstructive pulmonary disease; NIV = noninvasive ventilation.

The duration of the intervention varied from a minimum of four weekly sessions to a maximum of eight according to the needs of the patient. Each session lasted about 45 minutes, and participants received some homework to facilitate daily self-practice. Analogue sessions were conducted in a hospital setting or at the patients’ house or via telemedicine if patients were unable to attend the hospital.

Educational Intervention

The control group spent six sessions watching videos related to COPD management (i.e., improve the ability to cope with illness, benefit from exercise training programs, information about the common causes of exacerbations, smoking cessation, dietary habits; Figure 1). Moreover, participants attended physicians as per usual practice. Each session lasted about 30 minutes, and a psychologist was present for support.

Statistical Analysis

Frequency and descriptive analyses were performed for all the variables considered in the study for the overall sample and both the experimental and control groups. All continuous variables were tested for the normalcy of the distributions at each time. To assess the effects of the intervention immediately and over time, accounting for missing data and a loss of follow-up of at least 15% for 3 months, a 1:1 allocation ratio, primary outcome analysis implemented mixed-effects modeling, including mixed-model analysis of variance for linear data (63). In 2016, slower recruitment than predicted led us to reduce the analyzable sample size to 90, still sufficient to detect an effect size of 45 per group with 99.6% power at 5% (noncentrality parameter λ = 22.5; critical F = 3.94). Pairwise contrasts from the mixed-effects models were used to evaluate between-group differences. Pattern mixture models assessed whether estimates in the mixed-effects models were dependent on missing data patterns. In particular, simple mixed-effects models (also known as multilevel models, random-effects model, and hierarchical models) with a heterogeneous compound symmetry correlation structure among repeated measures were used to compare baseline and 3, 6, and 12 monthly scores on the effectiveness and differences between prescribed and effective hours of NIV, as well as on QoL both with or without considering covariates. This model was first done unconditionally, then with disease and psychological characteristics as covariates. Bonferroni correction was applied. Before model estimation, distributions of all outcome variables and random-effects residuals were inspected and deemed to be close approximations of normality. Using the absolute median deviation method to detect outliers, we found that no data points were deemed to be extreme (64). The analysis was performed using the intention-to-treat procedure. The significance level was 5% (p ≤ .05) and a two-tailed difference. Data analysis used the Statistical Package for Social Science (SPSS) software (version 23).

RESULTS

Participants Characteristics at Baseline and Study Period

A total of 108 patients with COPD met the eligibility criteria (Figure 1). Eight of these patients declined to take part in the study, whereas 10 of them refused to try NIV after it had been imposed on them in the acute phase and they did not even want to start the adaptation.

Ninety participants (mean [standard deviation] age = 76.20 [8.03] years; 51.11% male) were randomly allocated to the psychological support (n = 45, experimental group), or they were called to watch videos related to their illness management (n = 45, control group).

Baseline characteristics were similar by group and are summarized by descriptive comparisons following CONSORT guidelines (Tables 1, 2), notably estimates with 95% confidence interval (CI) representing two-tailed tests at a 5% significant level (65).

TABLE 1

Participant Characteristics of the Overall Sample and of Both the Experimental and Control Groups at the Baseline

Sociodemographic Characteristics
Variable	Overall Sample (n = 90)	Experimental Group (n = 45)	Control Group (n = 45)	p
Sex, M/F (% male)	46/44 (51.11)	20/25 (44.4)	26/19 (57.8)	.21
Age, mean (SD), y	76.20 (8.03)	76.71 (7.62)	75.69 (8.47)	.55
Marital status, n (%)				.73
Single	7 (7.77)	3 (6.7)	2 (4.4)
Married	57 (63.33)	30 (66.7)	27 (60)
Widower	18 (20)	7 (15.6)	11 (24.4)
Separated	3 (3.33)	3 (6.7)	0
Divorced	1 (1.11)	0	1 (2.2)
Without any family or social support	2 (2.22)	1 (2.2)	1 (2.2)
Cohabitants, n (%)				.28
Spouse	47 (52.22)	25 (27.77)	22 (24.44)
Mather	1 (1.1)	1 (2.2)	0
Father	0	0	0
Sons	9 (10)	4 (8.9)	5 (11.1)
Other relatives	2 (2.22)	2 (4.4)	0
Carer	1 (1.1)	1 (2.2)	0
Friends	0	0	0
Senior center	1 (1.1)	0	1 (2.2)
Alone	18 (20)	7 (15.55)	11 (12.22)
Spouse and carer	1 (1.1)	1 (2.2)	0
Spouse and sons	8 (8.88)	4 (8.9)	4 (8.9)
Educational level, n (%)				.81
None	6 (6.66)	4 (8.9)	2 (4.4)
Primary school	29 (32.22)	14 (31.1)	15 (33.3)
Secondary school	20 (22.22)	8 (17.8)	12 (26.7)
High school	23 (25.55)	12 (26.7)	11 (24.4)
Bachelor’s degree	1 (1.11)	1 (2.2)	0
Master’s degree	9 (10)	5 (11.1)	4 (8.9)
Working area, n (%)				.81
Craft industry	4 (4.44)	2 (4.4)	2 (4.4)
Business sector	7 (7.77)	3 (6.67)	4 (8.9)
Housewives	9 (10)	6 (13.3)	3 (6.7)
Industrial chemistry	4 (5.55)	3 (6.7)	2 (4.4)
Desk jobs	28 (31.11)	16 (35.6)	12 (26.7)
Workers	17 (18.88)	6 (13.3)	11 (24.4)
Food service industry	2 (2.22)	1 (2.2)	1 (2.2)
Health care	4 (4.44)	2 (4.4)	2 (4.4)
Construction industry	3 (3.33)	1 (2.2)	2 (4.4)
Transport	4 (4.44)	1 (2.2)	3 (6.7)
More areas	4 (4.44)	3 (6.7)	1 (2.2)
Mean length of illness, n (%)				.61
About 5 y	31 (34.44)	15 (33.3)	16 (35.6)
6–14 y	36 (40)	20 (44.4)	16 (35.6)
>15 y	19 (21.11)	9 (20)	10 (22.2)
Exacerbations during the last year, n (%)				.15
None	49 (54.4)	21 (46.7)	28 (62.2)
1–3	29 (32.22)	18 (40)	11 (24.4)
>3	9 (10)	5 (11.1)	4 (8.9)
Hospitalizations last year, n (%)				.597
<1	44 (48.88)	21 (46.7)	23 (51.1)
2	29 (32.22)	13 (28.9)	16 (35.6)
>2	14 (15.55)	9 (20)	5 (11.1)
Assistance during the last year, n (%)				.49
Yes	15 (16.66)	9 (20)	6 (13.3)
None	70 (77.77)	35 (77.8)	35 (77.8)
Type of assistance (if received), n (%)				.50
Senior center	1 (1.1)	0	1 (2.2)
Day care	1 (1.1)	1 (2.2)	0
Nurse	7 (7.77)	4 (9.5)	3 (7.1)
Physiotherapy	4 (4.44)	2 (4.4)	2 (4.4)
Other (i.e., clean)	2 (2.22)	2 (4.4)	1 (2.2)
Smoking habits, n (%)				.35
Yes, active	13 (14.44)	4 (8.9)	9 (20)
No, never	10 (10)	7 (15.6)	3 (6.7)
Ex	60 (66.66)	30 (71.1)	30 (66.7)
Pack/year, n (%)				.123
<10	4 (4.44)	4 (8.9)	0
10–20	24 (26.66)	15 (33.3)	9 (20)
>20	47 (52.22)	17 (37.8)	30 (66.7)
Alcohol habits, n (%)				.06
Never	37 (41.11)	22 (48.9)	15 (33.3)
Rarely	20 (23.33)	10 (22.2)	10 (22.2)
Sometimes	20 (23.33)	9 (20)	11 (24.4)
Quite often	0	0	0
Almost always	1 (1.1)	2 (4.4)	0
Always	4 (4.44)	0	4 (8.9)
Physical activity, n (%)				.07
Never	31 (34.44)	19 (42.2)	14 (31)
Rarely	15 (16.66)	8 (17.8)	7 (15.6)
Sometimes	13 (14.44)	8 (17.8)	5 (11.11)
Quite often	16 (17.77)	8 (17.8)	8 (17.8)
Almost always	4 (4.44)	0	4 (8.9)
Always	2 (2.22)	0	2 (4.4)
Medications, n (%)
LABA	60 (66.66)	27 (60)	33 (73.30)	.13
LAMA	49 (54.44)	26 (57.8)	23 (51.1)	.86
ICS	62 (72.22)	29 (64.4)	36 (80)	.06
Anxiolytics	25 (27.77)	15 (33.3)	10 (22.2)	.22
Antidepressants	20 (23.33)	14 (31.1)	7 (15.6)	.10
No. medication, mean (SD)	7.94 (4.78)	8.60 (3.87)	7.29 (5.50)	.19
No. comorbidities, mean (SD)	2.78 (1.42)	2.88 (1.31)	2.69 (1.53)	.63
BMI, mean (SD), kg/m2	29.45 (7.91)	30.06 (8.96)	28.85 (6.76)	.49

n = number of subjects; M = male; F = female; SD = standard deviation; LABA = long-acting β2-agonists; LAMA = long-acting muscarinic antagonist; ICS = inhaled corticosteroids; BMI = body mass index.

TABLE 2

COPD-Related Medical and Clinical Characteristics and Psychological Measures of the Overall Sample and of Both the Experimental and Control Groups at the Baseline

Variable	Overall Sample (n = 90)	Experimental Group (n = 45)	Control Group (n = 45)	p Values (ANOVA)
Medical and clinical characteristics
NIV hours, mean (SD)
Prescribed hours	8.57 (2.21)	8.90 (1.76)	8.20 (2.59)	.22
Effective hours	6.21 (3.30)	6.86 (3.15)	5.56 (3.35)	.59
Difference	1.89 (2.73)	1.67 (2.56)	2.11 (2.90)	.39
ADL, mean (SD)	0.99 (1.74)	1.18 (1.88)	0.77 (1.56)	.33
IADL, mean (SD)	3.16 (1.48)	3.20 (1.37)	3.10 (1.61)	.76
FSS, mean (SD)	45.27 (14.18)	48.82 (12.55)	41.37 (14.98)	.45
Spirometry, mean (SD)
FEV1	1.23 (0.71)	1.15 (0.69)	1.20 (0.62)	.75
FEV1%	50.71 (27.01)	49.74 (29.48)	51.74 (25.51)	.32
FVC	1.88 (0.86)	1.73 (0.84)	2.04 (0.86)	.11
FVC%	63.66 (24.77)	60.78 (25.39)	66.62 (24.08)	.30
FEV1/FVC	0.65 (0.36)	0.62 (0.17)	0.69 (0.49)	.51
FEV1/FVC%	63.95 (18.36)	62.56 (17.96)	65.24 (18.29)	.76
EGA, mean (SD)
pH	7.42 (0.04)	7.41 (0.04)	7.42 (0.04)	.46
Pao2	69.17 (10.78)	69.66 (9)	68.65 (12.48)	.67
Paco2	47.86 (10.16)	50.04 (10.86)	45.57 (8.95)	.14
HCO3	31.36 (7.67)	32.88 (8.63)	29.77 (6.24)	.07
Psychological and cognitive features
HADS, mean (SD)
Tot.	11.92 (7.21)	13.20 (7.36)	10.55 (6.86)	.09
HADS-A	7 (4.81)	8.07 (4.72)	5.86 (4.70)	.17
HADS-D	4.97 (3.48)	5.13 (3.64)	4.79 (3.34)	.64
EQ-5D, mean (SD)
Algorithm	0.23 (0.52)	0.13 (0.57)	0.34 (0.46)	.06
VAS	57.29 (21.91)	53.04 (20.36)	61.73 (22.82)	.07
QAF, mean (SD)
Tot.	53.61 (7.27)	49.98 (13.80)	49.38 (16.51)	.85
B-IPQ, mean (SD)	37.07 (12.63)	36.68 (9.76)	37.46 (13.63)	.43
ROSES, mean (SD)	30.41 (7.07)	29.48 (7.13)	31.37 (6.96)	.23
Cognitive variables
MMSE, mean (SD)	24.49 (7.04)	24.76 (6.48)	25.95 (4.11)	.72
MMSE Adj., mean (SD)	24.72 (3.44)	24.22 (7.62)	24.58 (3.95)	.52
ACE-R, mean (SD)
Tot.	72.85 (18.64)	74.63 (15.34)	71.07 (21.48)	.38
Tot. Adj.	76.62 (27.81)	82.03 (21.87)	71.21 (32.03)	.06
DI, mean (SD)	2.91 (3.44)	3.40 (3.52)	2.38 (3.31)	.18
CAM, n (%)
0.91
Yes	28 (31.11)	18 (40)	10 (22.2)
No	53 (58.88)	24 (57.1)	29 (64.4)

COPD = chronic obstructive pulmonary disease; n = number of subjects; ANOVA = analysis of variance; SD = standard deviation; ADL = activities of daily living; IADL = instrumental activities of daily living; FSS = Fatigue Severity Scale; FEV1 = forced expiratory volume in the first second; FVC = forced vital capacity; FEV1/FVC = ratio between forced expiratory volume in the first second and forced vital capacity or Tiffeneau Index; EGA = hemogasanalysis; pH = potential of hydrogen; Pao2 = partial pressure of oxygen in arterial blood; PaCO2 = partial pressure of carbon dioxide in arterial blood; HCO3 = hydrogen carbonate concentration; HADS = Hospital Anxiety and Depression Scale; Tot. = total score; HADS-A = Hospital Anxiety and Depression Scale—Anxiety; HADS-D = Hospital Anxiety and Depression Scale—Depression; EQ-5D = EuroQoL-5D Questionnaire; VAS = visual analog scale; QAF = Questionnaire on Adhesion to Pharmacological and Dietetic Therapy; B-IPQ = Brief Illness Perception Questionnaire; ROSES = Rosenberg’s Self-Esteem Scale; MMSE = Mini-Mental Status Examination; MMSE Adj. = Mini Mental Status Examination corrected; ACE-R = Addenbrooke’s Cognitive Examination Test—Revised; Tot. Adj. = total score adjusted; DI = Delirium Index; CAM = Confusion Assessment Method.

Participants had similar baseline characteristics to those who declined to try NIV or to take part in the study, and the most common reason for refusal to participate in the trial was time constraints.

Response Rate and Missing Data Patterns

The response rate at each assessment is reported in the flowchart (Figure 2). At 3 months (T1), 62 patients took part in the assessment, with a dropout rate of 31.11% (23 patients from the control group and 5 from the experimental group). The response rate at 6 months (T2) was 44.44% (15 experimental group and 25 control group) and at 12 months (T3) was 32.22% (18 experimental group and 11 control group). Over the three-time point assessments, these dropout rates were mainly due to worsening clinical conditions (40%), missed clinical appointments due to physical ill-health (42.22%), or change in circumstances (1.11%). In six cases (6.66%), we had no information about the patient, and they were not reachable on the phone. Moreover, 17.77% of the COPD patients involved in the study died, whereas others were not yet due for follow-up (Figure 2).

FIGURE 2

CONSORT flowchart. CONSORT = Consolidated Standards of Reporting Trials; NIV = noninvasive ventilation.

Outcome Analysis

Table 3 shows the means and standard deviations of both patients’ clinical parameters and questionnaire scores at each measurement occasion. Independent mixed-effects models were estimated for each outcome measure. Each model included group (control, intervention) and measurement interval (preassessment, postassessment, follow-up) as fixed effects (i.e., in the form of an interaction predictor [group by interval]) and participant (within measurement Interval) as a random effect. This allowed a unique regression model (i.e., intercept and slope) to be specified for every participant across measurement intervals.

TABLE 3

Mean Scores on the Outcome Measures Over the Study Period

Outcome Measures	Follow-Up Assessment
	3 mo (T1)		6 mo (T2)		12 mo (T3)
	Experimental Group (n = 40)	Control Group (n = 22)	Experimental Group (n = 30)	Control Group (n = 20)	Experimental Group (n = 27)	Control Group (n = 34)
Medical and clinical characteristics
NIV hours, mean (SD)
Prescribed hours	8.63 (1.47)	7.78 (2.13)	8.87 (1.45)	8.52 (1.5)	8.73 (1.04)	8.41 (2.06)
Effective hours	6.11 (3.65)	3.83 (3.44)	4.16 (4.18)	2.69 (3.37)	8.02 (1.78)	6.15 (2.66)
Difference	0.73 (2.00)	1.51 (2.41)	0.64 (1.17)	0.98 (2.01)	0.35 (1.50)	0.84 (2.03)
ADL, mean (SD)	1.20 (1.77)	0.21 (0.60)	1.26 (1.94)	0.33 (0.80)	0.93 (1.68)	0.27 (0.57)
IADL, mean (SD)	3.01 (1.80)	2.91 (1.47)	3.33 (1.49)	2.71 (1.62)	3.18 (1.28)	2.88 (1.74)
FSS, mean (SD)	41.38 (13.94)	43.75 (14.45)	40.78 (13.53)	33.88 (16.01)	39.52 (13.76)	42.70 (12.03)
Spirometry, mean (SD)
FEV1	0.83 (0.41)	1.41 (0.77)	0.93 (0.29)	1.49 (0.81)	1.33 (0.77)	1.41 (1.02)
FEV1%	45.67 (18.4)	54.04 (23.70)	46.43 (21.67)	60.18 (30.05)	53 (30.58)	71.71 (43.11)
FVC	1.53 (0.61)	2.43 (0.85)	1.15 (1.20)	1.94 (0.69)	2.011 (0.85)	2.27 (1.65)
FVC%	56.24 (19.76)	71.85 (20.56)	63.92 (17.38)	68.90 (23.03)	68.26 (27.78)	72.50 (51.17)
FEV1/FVC	0.55 (0.97)	0.64 (0.20)	0.68 (0.11)	0.565 (0.11)	0.60 (0.18)	65.56 (10.82)
FEV1/FVC%	66.36 (15.18)	60.40 (29.08)	73.64 (23.77)	74.44 (23.34)	75.08 (20.93)	58.15 (28.27)
EGA, mean (SD)
pH	7.40 (0.03)	7.42 (0.05)	7.39 (0.55)	7.44 (0.03)	7.00 (0.00)	7.45 (0.03)
Pao2	65.53 (10.28)	71.21 (17.23)	64.90 (5.70)	63.78 (10.12)	69.53 (10.66)	70.20 (5.44)
PaCO2	52.20 (9.44)	50.29 (14.53)	52.00 (7.46)	58.89 (27.67)	47.30 (6.31)	41.60 (5.02)
HCO3	30.00 (9.62)	29.31 (5.01)	31.94 (13.71)	27.24 (10.14)	30.572 (4.49)	38.80 (12.49)
Psychological and cognitive features
Psychological variables
HADS, mean (SD)
Tot.	9.78 (5.81)	10.88 (8.05)	10.78 (6.51)	6.55 (5.27)	9.66 (6.48)	9.00 (6.37)
HADS-A	5.83 (4.17)	5.31 (5.23)	6.07 (4.12)	3.11 (3.82)	6.22 (4.41)	5.50 (5.01)
HADS-D	4.50 (1.91)	5.69 (3.53)	4.71 (2.86)	3.44 (2.78)	3.44 (2.89)	3.50 (2.17)
EQ-5D, mean (SD)
Algorithm	0.29 (0.40)	0.23 (0.62)	0.35 (0.349)	0.70 (0.48)	0.26 (0.35)	0.43 (0.51)
VAS	60.83 (20.88)	59.06 (15.97)	71.07 (16.54)	68.50 (15.28)	64.16 (15.55)	66 (13.49)
QAF, mean (SD)
Tot.	54.38 (4.10)	55.26 (5.20)	53.92 (6.78)	54.77 (5.33)	53.47 (6.69)	53.30 (5.12)
B-IPQ, mean (SD)	43.66 (7.53)	37.05 (14.80)	34.92 (14.31)	33.5 (9.02)	35.11 (13.02)	37.80 (13.00)
ROSES, mean (SD)	31.77 (5.96)	31.93 (6.12)	35.85 (3.61)	33.77 (3.52)	34.20 (3.12)	29.60 (8.82)
Cognitive variables
MMSE, mean (SD)	N/A	N/A	27.81 (1.60)	27.75 (1.50)	27.30 (2.25)	26.20 (3.56)
MMSE Adj., mean (SD)	N/A	N/A	26.42 (1.51)	27.33 (1.15)	26.72 (1.40)	25.00 (2.58)
ACE-R, mean (SD)
Tot.	N/A	N/A	84.30 (8.43)	79.5 (8.66)	78.76 (9.40)	75.80 (15.97)
Tot. ACE-R Adj.	N/A	N/A	92.70 (7.90)	96.25 (6.18)	87.75 (9.22)	86.40 (11.88)
DI, mean (SD)	2.11 (3.56)	0.53 (0.99)	0.88 (1.72)	0 (0.0)	0.78 (1.88)	0.25 (0.70)

n = number of subjects; NIV = noninvasive ventilation; SD = standard deviation; ADL = activities of daily living; IADL = instrumental activities of daily living; FSS = Fatigue Severity Scale; FEV1 = forced expiratory volume in the first second; FVC = forced vital capacity; FEV1/FVC = ratio between forced expiratory volume in the first second and forced vital capacity or Tiffeneau Index; EGA = hemogasanalysis; pH = potential of hydrogen; Pao2 = partial pressure of oxygen in arterial blood; Paco2 = partial pressure of carbon dioxide in arterial blood; HCO3 = hydrogen carbonate concentration; HADS = Hospital Anxiety and Depression Scale; Tot. = total score; HADS-A = Hospital Anxiety and Depression Scale—Anxiety; HADS-D = Hospital Anxiety and Depression Scale—Depression; EQ-5D = EuroQoL-5D Questionnaire; VAS = visual analog scale; QAF = Questionnaire on Adhesion to Pharmacological and Dietetic Therapy; B-IPQ = Brief Illness Perception Questionnaire; ROSES = Rosenberg’s Self-Esteem Scale; MMSE = Mini-Mental Status Examination; N/A = not applicable; MMSE Adj. = Mini Mental Status Examination corrected; ACE-R = Addenbrooke’s Cognitive Examination Test—Revised; DI = Delirium Index.

According to the objectives and outcomes explained previously, global scores for the participants were reported using mixed methods.

Test of the Intervention on Primary Outcomes

Results from the estimated mixed-effects models show an overall good effect of intervention compared with control for the primary outcome measures. Point estimates, 95% CIs of effect sizes, and summaries of each model are shown in Tables 4 and 5.

TABLE 4

Fixed-Effects Estimates (at Postassessment and Follow-Up Assessment Phases) and Per Groups With 95% CIs for Medical and Clinical Outcome Measures

Outcome Measures	Value	SE	Cls	t	p
NIV hours
Prescribed hours
(Intercept)	8.67	0.122	8.43 to 8.91	71.137	<.001
3-mo follow-up	−0.087	0.302	−0.67 to 0.505	−0.288	.77
6-mo follow-up	0.0509	0.341	−0.618 to 0.720	0.149	.89
12-mo follow-up	0.0585	0.444	−0.812 to 0.929	0.132	.91
(Intercept)	8.639	0.115	8.41 to 8.86	75.03	<.001
Group	0.451	0.23	4.81 to 5	1.96	.05
Effective hours
(Intercept)	7.134	0.75	5.665 to 8.60	10	.07
3-mo follow-up	0.94	0.035	0.87 to 1.01	26.62	.000
6-mo follow-up	−1.02	0.35	−1,73 to −0.31	−2.9	.006
12-mo follow-up	1.283	0.52	0.235 to 2.27	2.412	0.026
(Intercept)	6.261461	0.2514	5.76 to 6.75	24.901	<.000
Group	1.5259	0.3389	0.85 to 2.19	4.503	<.000
Difference
(Intercept)	1.55	0.511	0.54 to 2.55	3.035	.20
3-mo follow-up	−0.399	0.5	−0.38 to −1.58	−0.798	.49
6-mo follow-up	−0.34	0.483	−1.28 to −0.60	−0.704	.51
12-mo follow-up	−1.386	0.527	−2.41 to −0.35	−2.629	.029
(Intercept)	1.63	0.264	1.11 to 2.15	6.18	.013
Group	−1.05	0.351	−1.64 to −0.36	−3.01	.007
FSS
(Intercept)	41.73	1.7	38.4 to 45.06	24.534	.011
3-mo follow-up	−2.57	5.39	−13.1 to 7.99	−0.477	.71
6-mo follow-up	−7.87	3.28	−14.3 to −1.44	−2.399	.023
12-mo follow-up	−3.84	5.65	−14.9 to 7.24	−0.679	.61
(Intercept)	42.3	1.52	39.32 to 45.28	27.81	<.001
Group	2.56	2.78	−2.89 to 8.01	0.921	.40
Spirometry
FEV1
(Intercept)	7.63	0.881	5.90 to 9.36	8.66	<.001
3-mo follow-up	−5.77	1.413	−8.54 to −3.00	−4.08	<.001
6-mo follow-up	−6.27	0.897	−8.03 to −4.51	−6.99	<.001
12-mo follow-up	0	0	0	0	0
(Intercept)	1.73	0.36	1.01 to 2.45	4.71	.66
Group	3.67	3.39	−2.97 to 10.32	1.08	.29
FEV1%
(Intercept)	49.96	3.69	42.7 to 57.2	13.5388	.05
3-mo follow-up	−0.0906	7.72	−15.2 to 15	−0.0117	.99
6-mo follow-up	−2.6516	6.7	−15.8 to 10.5	−0.3961	.72
12-mo follow-up	0.9961	6.54	−11.8 to 13.8	0.1522	.88
(Intercept)	50.44	2.04	46.4 to 54.4	24.67	<.001
Group	−6.55	4.09	−14.6 to 1.46	−1.6	.111
FVC
(Intercept)	2.733	0.361	2.02 to 3.44	7.572	<.001
3-mo follow-up	1.48	1.009	−0.49 to 3.46	1.467	.16
6-mo follow-up	1.3	1.236	−1.122 to 3.72	1.052	.30
12-mo follow-up	0.153	0.747	−1.310 to 1.62	0.205	.84
(Intercept)	2.531	0.381	1.78 to 3.27	6.643	.073
Group	−0.327	0.476	−1.26 to 0.606	−0.687	.53
FVC%
(Intercept)	62	2.74	56.6 to 67.4	22.601	.008
3-mo follow-up	−1.44	2.74	−15.8 to 12.9	−0.196	.87
6-mo follow-up	−3.38	7.11	−17.3 to 10.5	−0.476	.69
12-mo follow-up	−3.4	7.77	−18.6 to 11.8	−0.438	.74
(Intercept)	63.51	1.92	59.8 to 67.27	33.12	<.001
Group	−6.46	3.83	14 to 1.06	−1.68	.094
FEV1/FVC
(Intercept)	61.54	3.38	54.9 to 68.2	18.193	<.001
3-mo follow-up	−6.85	14.24	−34.8 to 21.1	−0.481	.71
6-mo follow-up	−10.44	15.31	−40.4 to 19.6	−0.682	.59
12-mo follow-up	−4.68	13.3	−30.8 to 21.4	−0.352	.78
(Intercept)	60.99	2.38	56.3 to 65.66	25.625	<.001
Group	−4.1	−13.4	−13.4 to 5.23	−0.861	.39
FEV1/FVC%
(Intercept)	70.313	2.15	66.10 to 74.5	32.7048	<.001
3-mo follow-up	8.438	6.63	−4.56 to 21.4	1.2722	.39
6-mo follow-up	12.39	7.06	−1.44 to 26.2	1.7558	.23
12-mo follow-up	0.555	10.94	−10.89 to 22	0.0507	.97
(Intercept)	70.53	3.14	64.4 to 76.68	22.463	<.001
Group	−4.09	5.18	−14.2 to 6.06	−0.789	.56
ABG or EGA
pH
(Intercept)	7.42	0.005	7.40 to 7.43	1245.11	<.001
3-mo follow-up	−0.004	0.009	−0.0236 to 0.0143	−0.4824	.64
6-mo follow-up	0.001	0.022	−0.04 to 0.0453	0.0822	.95
12-mo follow-up	0.001	0.024	−0.04 to 0.0455	0.0824	.95
(Intercept)	7.42	0.003	7.41–7.42	1905.16	<.001
Group	−0.017	0.01	−0.03 to 0.003	−1.62	.36
Pao2
(Intercept)	68.01	1.06	65.94–70.08	64.27	<.001
3-mo follow-up	0.528	3.55	7.48	0.1487	.90
6-mo follow-up	−4.84	2.8	0.642	−1.7305	.11
12-mo follow-up	−0.277	2.8	5.210	−0.0988	.92
(Intercept)	68.671	0.991	66.73–70.61	69.278	.003
Group	−0.777	2.084	−4.86 to 3.31	−0.373	.75
Paco2
(Intercept)	50.02	1.11	47.85–52.19	45.141	<.001
3-mo follow-up	3.51	2.78	−1.94 to 8.96	1.263	.33
6-mo follow-up	8.12	6.81	−5.24 to 21.47	1.191	.47
12-mo follow-up	−2.84	2.95	−8.63 to 2.95	−0.961	.34
(Intercept)	49.97	2.36	45.35–54.58	21.208	<.001
Group	1.37	3.28	−5.06 to 7.80	0.418	.71
HCO3
(Intercept)	34.5	2.6	29.40–39.60	13.26	.056
3-mo follow-up	−2.79	2.72	−8.11 to 2.53	−1.03	.44
6-mo follow-up	−2.44	2.18	−6.72 to 1.84	1.12	.42
12-mo follow-up	9.05	7.78	−6.20 to 24.29	1.16	.45
(Intercept)	34.43	2.61	29.3–35.55	13.198	.006
Group	−4.11	4.16	−12.3 to 4.04	−0.988	.42

CIs = confidence intervals; SE = standard error; NIV = noninvasive ventilation; FSS = Fatigue Severity Scale; FEV1 = forced expiratory volume in the first second; FVC = forced vital capacity; FEV1/FVC = ratio between forced expiratory volume in the first second and forced vital capacity or Tiffeneau Index; ABG = arterial blood gas; EGA = hemogasanalysis; pH = potential of hydrogen; Pao2 = partial pressure of oxygen in arterial blood; Paco2 = partial pressure of carbon dioxide in arterial blood; HCO3 = hydrogen carbonate concentration.

TABLE 5

Fixed-Effects Estimates (at Postassessment and Follow-Up Assessment Phases) With 95% CIs for Psychological and Cognitive Outcome Measures

Outcome Measures	Value	SE	Cls	t	p
Psychological variables
HADS
Tot.
(Intercept)	10.09	0.91	8.31 to 11.87	11.09	0.042
3-mo follow-up	−1.33	2.078	−5.41 to 2.73	−0.642	0.62
6-mo follow-up	−3.09	1.708	−6.44 to 0.259	−1.808	0.16
12-mo follow-up	−2.27	1.772	−5.45 to 1.198	−1.284	0.35
(Intercept)	10.41	0.706	9.02 to 11.80	14.74	<.001
Group	1.4	1.089	−0.730 to 3.54	1.29	0.23
HADS-A
(Intercept)	5.715	0.823	4.10 to 7.32	6.943	0.088
3-mo follow-up	−1.278	1.184	−3.60 to 1.043	−1.079	0.042
6-mo follow-up	−2.293	1.09	−4.43 to −0.157	−2.104	0.079
12-mo follow-up	−0.978	1.18	−3.29 to 1.334	−0.829	0.50
(Intercept)	5.9	0.492	4.93 to 6.86	11.98	<.001
Group	1.54	0.702	0.167 to 2.92	2.2	0.039
HADS-D
(Intercept)	4.43	0.277	3.89 to 4.97	15.99	<.001
3-mo follow-up	0.061	0.914	−1.73 to 1.85	0.0675	0.96
6-mo follow-up	−0.082	0.835	−2.47 to 0.80	−0.9935	0.40
12-mo follow-up	−1.3592	0.748	−2.83 to 0.107	−1.81	0.15
(Intercept)	4.56	0.327	3.92 to 5.202	13.967	0.005
Group	−0.058	0.496	−1.03 to 0.914	−0.117	0.91
EQ-5D
Algorithm
(Intercept)	1.07	0.901466	−0.70 to 2.84	1,188	0.23
3-mo follow-up	0.1108	1.01	−1.93 to 2.15	0.109	0.91
6-mo follow-up	−0.41	1.02	−2.42 to 1.59	−0.405	0.68
12-mo follow-up	−0.31	1.01	−2.31 to 1.68	−0.31	0.75
(Intercept)	0.58	0.114137	0.36 to 0.81	5.15	<.000
Group	-0.40	0.1535	−0.70 to −0.10	−2.631	<.009
VAS
(Intercept)	62.68	1.72	59.30 to 66	36.46	<.001
3-mo follow-up	2.58	6.03	−9.23 to 14.4	0.428	0.73
6-mo follow-up 6-mo follow-up	12.46	6.68	−0.62 to 25.6	1.866	0.28
12-mo follow-up	6.19	5.72	−5.02 to 17.4	1.082	0.44
(Intercept)	62.21	3.85	57.12 to 67.30	23.96	<.001
Group	−1.57	3.85	−9.13 to 5.98	−0.408	0.70
QAF
Tot.
(Intercept)	54.10	0.494	53.14 to 55.08	109.53	<.001
3-mo follow-up	0.986	1.159	−1.29 to 3.26	0.851	0.40
6-mo follow-up	0.325	1.327	−2.28 to 2.93	0.244	0.81
12-mo follow-up	−0.448	1.248	−2.89 to 2	−0.359	0.72
(Intercept)	54.09	0.437	53.24 to 54.95	123.83	<.001
Group	−0.66	0.874	−2.38 to 1.05	−0.762	0.45
B-IPQ
(Intercept)	38.51	1.93	34.73 to 42.29	19.984	0.026
3-mo follow-up	−2.09	2.55	−7.08 to 2.90	−0.822	0.046
6-mo follow-up	−7.95	4.78	−17.32 to 1.42	−1.663	0.33
12-mo follow-up	−5.79	6.42	−18.36 to 6.79	−0.902	0.53
(Intercept)	351.153	1.8192	31.51 to 38.72	19.302	.000
Group	73.10	2.4761	2.40 to 12.21	2.953	.004
ROSES
(Intercept)	32.92	0.419	32.10 to 33.74	78.65	<.001
3-mo follow-up	1.53	1.329	−1.072 to 4.14	1.15	0.41
6-mo follow-up	3.72	1.494	0.796 to 6.65	2.49	0.16
12-mo follow-up	0.055	2.55	−4.94 to 5.06	0.02	0.99
(Intercept)	32.81	0.759	31.32 to 34.3	43.2	<.001
Group	0.803	1.25	−1.65 to 3.25	0.64	0.56
Cognitive variables
MMSE
(Intercept)	26.7	0.909	25.18 to 28.75	29.66	<.001
3-mo follow-up	1.06	3.441	−5.68 to 7.8	0.308	0.76
6-mo follow-up	2	0.932	0.17 to 3.82	2.141	0.034
12-mo follow-up	1.06	0.888	−0.8 to 2.8	1.193	0.23
(Intercept)	26.73	0.581	25.59 to 27.87	45.97	<.001
Group	0.183	0.636	−2.49	0.287	0.77
MMSE Adj.
(Intercept)	26.973	0.944	25.12 to 28.82	28.568	0.995
3-mo follow-up	1.591	3.711	−5.68 to 8.86	0.429	1
6-mo follow-up	1.583	2.102	−2.54 to 5.7	0.753	0.46
12-mo follow-up	−0.949	2.406	−5.66 to 3.77	−0.394	0.76
(Intercept)	26.29	0.69	24.93 to 27.65	37.96	<.001
Group	1.32	1.58	−1.79 to 4.43	0.83	0.51
ACE-R
Tot.
(Intercept)	78.49	4.13	70.41 to 86.6	19.02	0.37
3-mo follow-up	4.11	15.59	−26.44 to 34.7	0.26	0.90
6-mo follow-up	10.24	4.34	1.73 to 18.7	2.36	0.02
12-mo follow-up	4.05	4.02	−3.83 to 11.9	1.007	0.32
(Intercept)	77.53	2.85	71.95 to 83.12	27.21	0.002
Group	1.71	2.94	−11.52	0.582	0.57
DI
(Intercept)	1.27	0.494	0.305 to 2.24	2.58	0.23
3-mo follow-up	−1.54	0.638	−2.78 to −0.28	−2.41	0.099
6-mo follow-up	−2.39	0.629	−3.62 to −1.61	−3.81	<.001
12-mo follow-up	−2.41	0.669	−3.72 to −1.10	−3.61	0.022
(Intercept)	1.307	0.607	0.11 to 2.50	2.15	0.11
Group	0.93	0.439	0.07 to 1.79	2.12	0.036

CIs = confidence intervals; CG=Control Group; SE = standard error; HADS = Hospital Anxiety and Depression Scale; Tot. = total score; HADS-A = Hospital Anxiety and Depression Scale—Anxiety; HADS-D = Hospital Anxiety and Depression Scale—Depression; EG= Experimental Group; EQ-5D = EuroQoL-5D Questionnaire; VAS = visual analog scale; QAF = Questionnaire on Adhesion to Pharmacological and Dietetic Therapy; B-IPQ = Brief Illness Perception Questionnaire; ROSES = Rosenberg’s Self-Esteem Scale; MMSE = Mini Mental Status Examination; MMSE Adj. = Mini Mental Status Examination corrected; ACE-R = Addenbrooke’s Cognitive Examination Test—Revised; DI = Delirium Index.

Bold indicates statistically significant.

NIV Hours

Using the mean of effective weekly NIV hours as a dependent variable in the mixed-effects model, without adding any covariate, the difference between preintervention and postintervention scores was significant (F(64.410) = 8.558, p = .005). The intervention had a significant impact (F(304) = 19.054, p < .001) between groups, which was not maintained when both the mentioned covariates were added. However, in this case, both the prescribed hours (F(205.787) = 22.434, p < .001) and the difference between them and the effective NIV hours practiced (F(71.476) = 8.991, p = .004) significantly impacted the mean of the effective hours. Moreover, in the model, if the difference between prescribed and effective NIV hours is used as a dependent variable, a significant difference between preintervention and postintervention scores appears (F(209.744) = 208.480, p < .001), and there was also a significant difference between groups (F(71.476) = 8.991, p = .004).

Test of the Intervention on Secondary Outcomes

Quality of Life

In the mixed-effects model without any covariates, QoL, assessed using the algorithm of the EuroQoL, showed significant difference in both groups (F(156) = 10.264, p = .002) and over time (F(71.480) = 8.114, p = .006). However, none of the covariate results or their interactions were significant.

Psychological Variables

Results from the mixed-effects models showed that, compared with control, the intervention resulted in a slight improvement in the HADS-A score (F(170) = 5.226, p = .023), which was not maintained over time (F(77.416) = 2.747, p = .101). Depression, as assessed by the subscale of the HADS, did not differ significantly between groups (F(50.101) = .042, p = .838) or over time (F(45.099) = .006, p = .939). Other relevant results are represented by the impact of the intervention on the Brief Illness Perception Questionnaire score over time (F(64.444) = 5.418, p = .023) and between groups (F(140) = 6.172, p = .014; compare with Table 5 for specific models). On the other hand, anxiety significantly influenced NIV effective hours overtime (F(75.783) = 2.764, p = .001) as well as between groups (F(102.946) = 2.410, p < .001). For depression, there was also an impact on the number of effective NIV hours (F(112.593) = 2.513, p = .003) between groups and over time (F(75.250) = 2.673, p = .003).

Cognitive Functions

Overall cognitive function scores significantly influenced both acceptance and adherence to NIV. In particular, the total scores of the ACE-R (F(14.453) = 5.140, p = .039), the MMSE (F(18.180) = 5.741, p = .028), and the Delirium Index (F(26.698) = 5.336, p = .029) significantly influenced the difference between the prescribed hours and the effective NIV hours over time, whereas the total score of the ACE-R had an impact on NIV adherence between groups (F(51.540) = 4.704, p = .035). In this context, their interactions were also significant. Moreover, the interaction between the MMSE and the ACE-R (F(49.675) = 5.123, p = .028) as well as between the ACE-R and the Delirium Index derived from the CAM (F(49.157) = 5.980, p = .018) influenced the number of effective NIV hours practiced.

The fixed-effects estimates at postassessment and follow-up assessment phases and per group with 95% CIs for medical and clinical outcome measures are shown in Table 4. Table 5 shows fixed-effects estimates (at postassessment and follow-up assessment phases) with 95% CIs for psychological and cognitive outcome measures.

DISCUSSION

Our study assessed the effectiveness of a short-term CBT intervention on NIV acceptance and adherence in patients with COPD. The intervention resulted in a significant and clinically important impact on groups in terms of NIV adherence and QoL, with a slight short-term improvement for anxiety. In this respect, it is relevant to note that there are no standard interventions to promote acceptance and adherence to medication or NIV in COPD people. There are only a few studies regarding this aspect, maybe because of its complexity and because previous research confirmed the importance of the combination of different components such as information, self-care management, counseling, family therapy, supportive care, or telephone follow-up. Therefore, the results are limited and mainly focused on the possible factors that influence acceptance or adherence (66). This, although representing an important strength of the study and opening the need for further research, does not allow for comparisons with other studies, also considering the cultural and social aspects of other realities.

Despite this limitation, the study allowed us to note that adherence to NIV is a very complex construct, influenced by several factors. These include a significant influence by cognitive function, the number of hours of NIV prescribed, and the difference between these hours and the hours performed. On the other hand, the difference between the prescribed and the effective hours of NIV and the weekly mean NIV hours had an impact on both anxiety and depression over time. It is important to note that the psychological intervention did not specifically aim to improve anxiety and depression, as they operate via different mechanisms. Moreover, their initial means were not clinically elevated at baseline. Therefore, it could be expected that the regression means are not significantly different.

In addition to its primary clinical effectiveness outcomes, our data show the potential for CBT to improve adaptation and adherence to NIV in patients with COPD as well as the access and engagement with psychotherapy in primary care. The majority of patients of the experimental group found the strategies to overcome the difficulties related to the NIV’s usage (i.e., mask fit, air leakage, and claustrophobia), thanks to the psychological intervention, which integrated them into their healthcare routine. These results stress the relevance of paying attention to the patients’ needs during the adaptation to a new device process that is suddenly perceived as another sign of limitation (67). Indeed, expectations are driven by not only medication but also the disease itself and the elaboration process of the information collected by the patients about it (68,69).

An integrated approach, focusing on the overall perceptions of the NIV’s impact on daily life and considering lifestyle factors, demographic characteristics (age, comorbidities, physical limitations, psychological and cognitive status), and pharmacological factors (polypharmacy regimens), should be promoted to optimize treatment adherence and perseverance as well as to prevent worsening clinical and economic outcomes.

Finally, it is interesting to note that the illness beliefs and perceptions influenced the intervention, underlying how it is relevant to provide a different perspective about the illness as well as reinforce the link between mind and body and their mutual relationship, as seen in other studies on medication adherence (70,71). Further studies might investigate if adherence is more connected to the beliefs regarding the illness than to the respiratory parameters, and therefore, the different trajectories between QoL, adherence, and functional and emotional status can be derived from a complex interaction of different variables such as perceived dyspnea levels expectations, beliefs, levels of an activity practice, motivation, cognitive functioning, and mood.

Strengths and Limitations

The study presents certain limitations. First, some characteristics of the design are important in interpreting the results. The randomized controlled trial, which is a meticulous study design, is in contrast with the patient-centered approach used in the intervention to pay attention to their needs. In particular, all the experimental members were biased regarding telemedicine, worrying about their lower levels of confidence with technology and condoning a personal and face-to-face relationship. In this regard, telemedicine can facilitate access to specialists and information avoiding difficult transportations, but the broadband connections can malfunction or run into other technological problems, reducing the practicability and the naturalness of the relationship. Difficult tradeoffs often have to be made in choosing a control or comparison group. In our study, a group of usual care could have been useful to control the confounding factors even better. The choice of an active control group was to draw causal conclusions about the efficacy of a psychological intervention. Second, both the psychological monitoring of adherence and clinical conditions and the statistical analysis can be impacted by the dropout during the follow-up assessments, which was especially difficult to avoid. Reasons for missing appointments were attributed to death or the general worsening of the patient’s health status. Previous psychological and rehabilitation studies that involved people with COPD confirmed similar dropout rates. As previous studies confirm, dropout rates or discontinuity in following rehabilitation programs in patients with COPD tend to be high and frequent. Depression, somatization, smoking, living alone, a lower fat-free mass, and lower confidence in treatment were found to be positively associated with discontinuity in continuing treatment (72–76). Finally, the sample size is underestimated and smaller than expected by the initial potential power analysis. Therefore, the results of the analysis, in particular those of T3, are to be interpreted with caution. It is also relevant to consider that the patients with COPD involved in our study represent only a narrow range of the overall population in need of NIV and of the COPD who use NIV in the world, limiting the generalizability of the data.

Notwithstanding these limitations, this study has the value of bringing attention to the psychological factors that can be involved during the adaptation’s process to an external and life-limiting device like NIV, taking into consideration the patient’s needs and health conditions. Moreover, therapists and staff were not influenced by their participation in the evaluation study (the so-called Hawthorne effect).

Future Directions

Further studies are needed to improve and extend the intervention proposed during the adaptation to the NIV process. Future research should focus on replication of our findings and dissemination in routine care in different settings. Our dissemination efforts for the introduction of psychological support during the adaptation’s process to NIV include the launching of an online platform for those who are interested in learning about the treatment and collaborations. It should be tested in other populations in need of NIV, comparing it with alternative models and considering the role of the caregivers and the healthcare professionals. Finally, the evaluation of the introduction of psychological support during this complicated process in terms of healthcare costs should be implemented (49,76).