This article was submitted to Respiratory Pharmacology, a section of the journal Frontiers in Pharmacology
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Optimal peak inspiratory flow rate (PIFR) is crucial for inhalation therapy in patients with chronic obstructive pulmonary disease (COPD). However, little is known about the impact of PIFR-guided inhalation therapy on the clinical outcomes among patients with varying severities of COPD. A PIFR-guided inhalation therapy, including PIFR assessment and PIFR-guided inhaler education, was introduced in a pay-for-performance COPD management program in National Taiwan University Hospital. Among 383 COPD patients, there was significant reduction in incidence of severe acute exacerbation in the PIFR-guided inhalation therapy (PIFR group) than conventional inhaler education (control group) (11.9 vs. 21.1%,
Inhalational drug administration and inhaled therapeutic agents play a major role in the pharmacological management of chronic obstructive pulmonary disease (COPD) (
Either inadequate or excessive inspiratory flow rate during inhalation therapy has negative impact on drug delivery (
Based on PIFR values, clinicians can instruct patients to inhale medication with precise inhalation force or prescribe inhaler with proper resistance. Nevertheless, the impact of PIFR-guided inhalation therapy on COPD patients has not been evaluated. We hypothesized that COPD patients would benefit from PIFR-guided inhalation therapy and have improved clinical outcome. This study was thus conducted to investigate the impact of PIFR-guided inhalation therapy on the incidence of exacerbation and all-cause mortality in COPD patients with continuous inhalation therapy.
In Taiwan, a pay-for-performance program for COPD patients was introduced by the National Health Insurance Administration since 2017, which involved the prospective documentation of patient’s evaluation results, medication prescriptions and the episodes of disease exacerbation. The diagnosis of COPD was made in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria that is defined as follows: post-bronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio (FEV1/FVC ratio) of less than 70%. The inhalers were prescribed by attending physicians and all patients received inhaler education from the same case manager. The inhaler education included demonstration of the steps of inhaler handling and subsequent practices under direct observation at intervals of one to three months.
The PIFR-guided inhalation therapy, including PIFR assessment and PIFR-guided inhaler education, was introduced since June 2018 (
Peak Inspiratory Flow Rate guided inhalation therapy; DPI: dry powder inhaler; SMI: soft mist inhaler; pMDI: pressurized metered dose inhaler; PIFR: peak inspiratory flow rate.
The patients demographics, results of pulmonary function tests, smoking status, severity of COPD (in accordance with the GOLD criteria), type of inhaler devices used, the inhaled medications and vaccination were documented. Acute exacerbations were classified into three categories, in accordance with the GOLD report, namely, mild (relieved by short acting bronchodilators), moderate (treatment involves antibiotics or oral corticosteroids, in addition to short acting bronchodilators) and severe (involves visits to the emergency department or situations that require hospitalization). Data pertaining to the timing of the occurrence of mild exacerbations were self-reported, whereas the dates pertaining to the episodes of moderate or severe exacerbations were gathered from the medical records. In addition, the time interval between the initial inhaler education and the first episode of disease exacerbation were analyzed. This study was approved by the institutional review board of the National Taiwan University Hospital (201905058RINB).
Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Difference in continuous variables were analyzed by means of the Mann-Whitney U test. The data are presented as numbers (percentages) and median (25th, 75th percentile). The present study considered a two-sided
A total of 383 patients with COPD were enrolled. Among them, 223 (58.2%) patients received conventional inhaler education (control group) and, after introduction of PIFR-guided inhalation therapy, 160 (41.8%) patients received PIFR-guided inhalation therapy (PIFR group). As shown in
Baseline characteristics of the study subjects.
Total ( |
PIFR group ( |
Control group ( |
|
|
---|---|---|---|---|
Age, year | 73.4 (65.8,78.7) | 73.3 (66.8,78.7) | 73.4 (65.6,78.8) | 0.798 |
Male | 351 (91.6) | 153 (95.6) | 198 (88.8) | 0.017 |
Weight, kg | 63 (55.0,70.0) | 63 (56.0,71.0) | 62 (53.7,69.0) | 0.175 |
Height, cm | 163.1 (159.3,168.0) | 164 (159.3,168.0) | 163 (159.3,167.4) | 0.322 |
Body mass index, kg/m2 | 23.1 (20.5,25.7) | 23.1 (20.6,25.8) | 23 (20.5,25.7) | 0.569 |
FEV1, L | 1.48 (1.19,1.86) | 1.50 (1.24,1.93) | 1.46 (1.15,1.80) | 0.144 |
FEV1, % predicted | 70.5 (56.5,83.4) | 71.9 (57.4,85.2) | 69.9 (56.5,82.6) | 0.523 |
Maximal inspiratory pressures, cmH2O | −75.6 (−55.0,−95.0) | −75.3 (−55.0,−93.0) | −75.9 (−57.0,−95.0) | 0.877 |
COPD GOLD group | 0.748 | |||
GOLD group A | 102 (26.6) | 44 (27.5) | 58 (26.0) | |
GOLD group B | 203 (53.0) | 85 (53.1) | 118 (52.9) | |
GOLD group C | 18 (4.7) | 9 (5.6) | 9 (4.0) | |
GOLD group D | 60 (15.7) | 22 (13.8) | 38 (17.0) | |
Current smoker | 106 (27.7) | 49 (30.6) | 57 (25.6) | 0.512 |
Inhaler type | 0.556 | |||
pMDI | 12 (3.1) | 5 (3.1) | 7 (3.1) | |
SMI | 62 (16.2) | 24 (15.0) | 38 (17.0) | |
DPI | 229 (59.8) | 94 (58.8) | 135 (60.6) | |
DPI+ (pMDI or SMI) | 60 (15.7) | 31 (19.4) | 29 (13.0) | |
SMI+pMDI | 16 (4.2) | 4 (2.5) | 12 (5.4) | |
DPI+DPI | 4 (1.0) | 2 (1.2) | 2 (0.9) | |
Medication | 0.399 | |||
LAMA | 94 (24.5) | 41 (25.6) | 53 (23.8) | |
LABA | 12 (3.1) | 7 (4.4) | 5 (2.2) | |
LAMA+LABA | 148 (38.6) | 55 (34.4) | 93 (41.7) | |
ICS+LABA | 54 (14.1) | 20 (12.5) | 34 (15.2) | |
ICS+LAMA | 1 (0.4) | 0 (0.0) | 1 (0.5) | |
ICS+LAMA+LABA | 74 (19.3) | 37 (23.1) | 37 (16.6) | |
Vaccination | ||||
Influenza | 260 (67.9) | 117 (73.1) | 143 (64.1) | 0.063 |
Pneumococcus | 241 (62.9) | 105 (65.6) | 136 (61.0) | 0.354 |
Data presented as n (%) or median (25th, 75th percentile). FEV1: forced expiratory volume in 1 s; GOLD: global initiative for chronic obstructive lung disease; pMDI: pressurised metered dose inhaler; SMI: soft mist inhaler; DPI: dry powder inhaler; LAMA: long-acting muscarinic antagonist; LABA: long-acting beta2 agonist; ICS: inhaled corticosteroid; PIFR: peak inspiratory flow rate. PIFR group: patients who received PIFR-guided inhalation therapy.
Among 160 patients in PIFR group, 79 (49.4%) patients had inappropriate initial PIFR. In those who use dry powder inhalers (DPI), 9 (16%) out of fifty-seven patients displayed inadequate PIFR. After the feedback to primary physician, the inhaler was substituted with another type of inhaler in six patients. On the contrary, 32 (56%) DPI users, 18 (90%) pMDI users and 26 (87%) SMI users displayed excessive PIFR, and after education, they performed optimal PIFR in the subsequent check-ups.
Compared to the control group, there was a significant reduction in the incidence (11.9 vs. 21.1%, relative risk 0.56,
Incidence of acute exacerbation of chronic obstructive pulmonary disease within one year among the patients in the PIFR group and control group. AE: acute exacerbation. RR: relative risk. CI: confidence intervals.
One year incidence rates and incidence rate ratios of acute exacerbation in respect of severity among the study subjects.
PIFR group ( |
Control group ( |
Incidence rate ratio (PIFR group to control group) |
|
|
---|---|---|---|---|
Total AE | 0.88 (0.71–1.06) | 1.14 (0.94–1.34) | 0.84 (0.62–1.13) | 0.245 |
Mild AE | 0.11 (0.06–0.16) | 0.17 (0.11–0.23) | 0.68 (0.37–1.23) | 0.203 |
Moderate AE | 0.55 (0.42–0.68) | 0.55 (0.28–0.57) | 1.11 (0.79–1.57) | 0.546 |
Severe AE | 0.18 (0.09–0.27) | 0.43 (0.28–0.57) | 0.52 (0.32–0.87) | 0.012 |
Moderate-severe AE | 0.77 (0.60–0.94) | 0.98 (0.79–1.16) | 0.88 (0.64–1.20) | 0.401 |
Data presented as mean (95% confidence intervals). AE: acute exacerbation. Incidence rate was calculated as events/patient/year. PIFR group: patients who received PIFR-guided inhalation therapy.
Kaplan-Meier time-to-event plot and log-rank test for time to first severe acute exacerbation among PIFR group and control group.
In univariable analysis using Cox’s proportional-hazards analysis, the introduce of PIFR guided inhalation therapy, higher BMI, FEV1 ≥ 50% (GOLD stage1&2), less exacerbation in previous one year (GOLD group AandB) and single inhaler usage were associated with reduced probability of severe acute exacerbation. Multivariable analysis showed that the introduce of PIFR-guided inhalation therapy (Hazard ratio, HR = 0.48, 95% confidence interval, CI = 0.28–0.83,
Factors associated with the risk of severe exacerbation within one year.
Univariable analysis | Multivariable analysis | |||||
---|---|---|---|---|---|---|
Hazard ratio | 95% CI |
|
Hazard ratio | 95% CI |
|
|
PIFR vs. control group | 0.49 | 0.28–0.84 | 0.009 | 0.48 | 0.28–0.83 | 0.008 |
Age, year | 1.01 | 0.98–1.03 | 0.626 | — | — | — |
Male gender | 0.90 | 0.39–2.09 | 0.811 | — | — | — |
BMI, kg/m2 | 0.93 | 0.87–0.99 | 0.046 | 0.96 | 0.90–1.03 | 0.239 |
GOLD stage (1&2 vs. 3&4) | 0.43 | 0.26–0.73 | 0.002 | 0.58 | 0.32–1.04 | 0.069 |
GOLD group (A&B vs. C&D) | 0.31 | 0.19–0.51 | <0.001 | 0.34 | 0.21–0.57 | <0.001 |
Multiple vs. single inhaler device | 1.78 | 1.05–3.02 | 0.031 | 1.46 | 0.83–2.57 | 0.194 |
ICS vs. no ICS | 1.457 | 0.89–2.39 | 0.135 | — | — | — |
Current smoker vs. quitted | 0.79 | 0.44–1.40 | 0.417 | — | — | — |
Vaccination | ||||||
Influenza | 0.87 | 0.52–1.46 | 0.603 | — | — | — |
Pneumococcus | 1.33 | 0.79–2.25 | 0.288 | — | — | — |
PIFR; peak inspiratory flow rate; PIFR group: patients who received PIFR-guided inhalation therapy; BMI: body mass index; GOLD: global initiative for chronic obstructive lung disease; ICS: inhaled corticosteroid; CI: confidence interval.
Forrest plot pertaining to the hazard ratios of the time interval to the first episode of severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) among the patients in the PIFR and control groups, stratified by subgroups. GOLD: Global Initiative for Chronic Obstructive Lung Disease; pMDI: pressurized metered dose inhaler; SMI: soft mist inhaler; DPI: dry powder inhaler.
In this retrospective analysis of prospectively collected data, we found COPD patients receiving PIFR-guided inhalation therapy have lower probability of experiencing severe acute exacerbation. The PIFR-guided inhalation therapy is especially beneficial to patients of older age, short body stature, COPD GOLD stage 1&2 (FEV1 ≥ 50% predicted of value), COPD GOLD group C&D (frequent exacerbation phenotype), and using multiple inhalers at the same time. To our knowledge, no study has been undertaken to evaluate the impact of PIFR-guided inhalation therapy during COPD treatment, making this the first.
The devices handling errors during inhalation therapy has been known as important risk factors that influence the occurrence of exacerbation of COPD (
In addition, improper PIFR is also a point of concern in using SMI and pMDI, particularly in untrained patients (
A study by Loh and colleagues showed among 123 patients, 64 (52%) had suboptimal PIFR and had greater scores in the COPD assessment test, more frequent re-admissions due to COPD within 90 days, and fewer days to re-admission after treatment initiation (
According to previous reports, several factors such as older age, female gender, short stature, reduced inspiratory capacity, inspiratory muscle weakness and acute status post exacerbation were strongly associated with suboptimal PIFR (
Furthermore, the PIFR-guided inhalation therapy may be particularly important in patients prescribed with a combination of different types of devices, such as DPI with SMI, DPI with pMDI or even two types of DPIs with different resistances. A previous study by Hira and colleagues analyzed the inhalation flow pattern in ten participants who were prescribed with a combination of DPI and SMI (
This study has certain limitations. Firstly, the predominance of the male gender, which is a feature of the population affected by COPD in Taiwan, may not represent the spectrum of the global population affected. Accordingly, several previous studies have reported that the female gender is an important predictor of reduced PIFR. In contrast, it was not observed to have significant effect in this study. Second, the data pertaining to the events of acute exacerbation in some patients may have been overlooked and were not included in the current retrospective analysis, especially the events that occurred in other hospitals. However, because all the patients were prospectively enrolled in the national COPD care program of Taiwan, most data pertaining to the relevant events and other medical details can be traced on the e-cloud system of National Health Insurance in Taiwan. Finally, without randomization and blindness, the present study may include confounding factors, such as the implementation of pulmonary rehabilitation (
Inappropriate PIFR during inhalation therapy is indeed an important factor in inhaler handling, thus the role of PIFR assessment had been put on emphasis in recent years and even proposed to be an emerging biomarker in COPD treatment (
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by National Taiwan University Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
SC, CH, HP, CY, and JC participated in data collection, analysis, and interpretation. HP, HT, and JC provided materials and technical support. SC, CH, HP, HT, CY, and JC participated in critical discussion of research design and review of the manuscript. SC, CH, and JC participated in the conception and design of the study and wrote the manuscript.
This study was supported by funding from the Ministry of Science and Technology, Taiwan (MOST 109-2314-B-002-182) and National Taiwan University Hospital Hsin-Chu Branch, Taiwan (110-HCH089).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank the staff of Department of Medical Research, National Taiwan University Hsin-Chu Hospital for their assistance in statistical analysis.
The Supplementary Material for this article can be found online at: