Changes in Peak Inspiratory Flow After Acute Bronchodilation: An Observational Study of Patients with Stable Chronic Obstructive Pulmonary Disease

Abstract

Introduction:

Identifying factors influencing peak inspiratory flow (PIF) is essential for aerosol drug delivery in stable patients with chronic obstructive pulmonary disease. While a minimum PIF for dry powder inhalers (DPIs) is established, acute bronchodilator (BD) effects on PIF remain unknown.

Materials and Methods:

An inspiratory flow meter (In-Check™ DIAL) was used to measure PIF in stable patients during a 24-week observational cross-sectional study. Additionally, bronchodilator responsiveness (BDR) was determined using the In-Check DIAL device and spirometry. Patients received four puffs of albuterol, and pre- and post-BD PIF, forced expiratory volume in one second (FEV₁), and forced vital capacity were measured. Sixty-three patients completed acute BDR data collection from July 31, 2019, to November 9, 2021. Primary endpoints were pre- and post-BD spirometry and PIF. Statistical analyses included PIF correlations with FEV₁. BD change was assessed according to inhaler resistance and sex (subgroup analysis).

Results:

Median patient age was 64.8 years, 85.7% were non-Hispanic White, and 57.1% were female. The median increase in absolute PIF (In-Check DIAL) was 5.0 L/min, and the % PIF change was 8.9%. With albuterol, 57.1% experienced a PIF BD change >5.0%, whereas 49.2% experienced a change >10.0%. Similarly, 55.6% experienced an FEV₁ BD change >5.0% and 28.6% had a >10.0% FEV₁ BD change with albuterol. PIF was weakly correlated with FEV₁ BD change (absolute; % PIF; r = 0.28 [p = 0.02]; r = 0.21 [p = 0.11]). Pre- and post-BD median PIF were 75.5 and 83.5 L/min for low-to-medium–resistance DPI and 45.0 and 52.0 L/min for high-resistance, respectively. The median increases in pre- and post-BD PIF were 9.0 L/min in males and 4.5 L/min in females. In contrast to when using the In-Check DIAL device, we observed no consistent bronchodilatory effects on PIF measured by spirometry.

Conclusions:

Using the In-Check DIAL device, ∼50% of patients experienced >10% PIF increase after acute BD, potentially enhancing medication lung deposition. Further research is required to understand PIF's impact on medication delivery. ClinicalTrials.gov Identifier: NCT04168775

Introduction

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death globally.¹ It represents an economic burden projected to rise due to an aging global population and continued exposure to risk factors.¹ Inhalation therapy using a bronchodilator (BD) is the most effective way to relieve the symptoms of COPD.^1,2 Inhaled medications can be delivered through pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers, or nebulizers.³ DPIs have an internal resistance, are breath-actuated devices, and require forceful inhalation to disperse powder into small particles.³

A key factor affecting optimal lung deposition of medication using DPIs is peak inspiratory flow (PIF).^2,4,5 PIF, measured in liters per minute (L/min), refers to the maximum flow rate achieved during inhalation.^6,7 The minimum and optimum PIF vary depending on the DPI resistance: Handihaler^® (high-resistance DPI [R5])^2,8 ranges from 20 to 30 L/min,⁶ whereas Diskus^® and Ellipta^® (low-to-medium–resistance DPIs [R2])⁸ range from 30 to 60 L/min.⁶

Patients with a PIF <60 L/min may struggle to inhale medication effectively, leading to poor treatment outcomes.^2,6,7,9,10 Lower PIF has also been shown to result in less bronchodilation in patients with asthma. Three studies using different inspiratory flow (IF)–dependent DPIs (Aerolizer^®, Turbuhaler^®, and Rotahaler^®) reported decreased acute bronchodilatory effects in pediatric patients with asthma with lower PIF.^11–13 Pharmacokinetic studies have also shown reduced levels of drug delivery assessed via blood or urine measurements in patients with asthma and COPD.^14,15

PIF is a good physiological measure, a predictive biomarker, and a surrogate for acceleration and maximal IF pressure in patients with COPD.^6,16 Moreover, PIF has the advantage of being easily measured, making it a convenient tool for assessing and monitoring respiratory function and assessing patients' ability to properly use DPIs.⁶ Therefore, comparing the same molecule(s) in different delivery systems with varying resistance among patients with different PIF statuses directly assesses PIF as a predictive biomarker for treatment outcomes.^16,17

Despite the critical role of PIF in DPI performance, there is limited information on the factors that affect PIF in ambulatory patients with COPD, particularly in the context of bronchodilator responsiveness (BDR).^2,3,17,18 The 2021 American Thoracic Society (ATS) and European Respiratory Society (ERS) technical standard for BDR is defined as >10% of the predicted value of forced expiratory volume in one second (FEV₁) or forced vital capacity (FVC).¹⁹

Further, standardized and reproducible PIF measurements are needed to ensure optimal drug delivery from DPIs, which requires a patient's ability to generate an optimal PIF.²⁰ To our knowledge, there is no guidance on incorporating acute bronchodilation effects into PIF measurements.

This study describes an a priori exploratory analysis originating from a larger observational study involving adults with spirometry-confirmed COPD. This cross-sectional analysis utilized single-visit measurements of pre- and post-BD PIF to investigate the clinical and patient factors influencing PIF in patients with COPD. Our primary endpoint was to measure pre- and post-BD spirometry and PIF. Subgroup analysis of the primary endpoint pre- and post-albuterol administration examined the association of bronchodilation change with inhaler resistance and sex.

Materials and Methods

Study design

Between July 31, 2019, and November 9, 2021, 80 of the 96 screened patients with COPD were enrolled in a study conducted at the University of North Carolina (UNC) Clinics. Pre- and post-BD lung function tests were performed on 63 patients with COPD. This study focused on baseline BDR in PIF. This analysis was part of a larger 24-week observational, cross-sectional study involving stable ambulatory adults with COPD using a DPI (ClinicalTrials.gov Identifier: NCT04168775).

The study protocol, informed consent forms, and other relevant documents were approved by the UNC at Chapel Hill (UNC-CH) Institutional Review Board (IRB No. 19-0450). Written informed consent was obtained from all patients, and all the study procedures adhered to the guidelines and regulations outlined by the UNC-CH IRB and the Declaration of Helsinki.

Study population

Eligible adults were aged >50 years with a spirometry-confirmed diagnosis of COPD (FEV₁/FVC ratio <0.70), had a history of current or former smoking (>10 pack-years of smoking), COPD severity of II–IV as assessed by the Global Initiative for Chronic Obstructive Lung Disease guidelines using existing spirometry results, a symptom severity score >10 on a COPD Assessment Test (CAT), COPD exacerbation requiring systemic corticosteroids within the past 3 years, a stable COPD (no recent exacerbations in the past 30 days), and prescription for a maintenance DPI. Patients were enrolled if they could achieve a PIF of 60–90 L/min against R2 DPIs (Diskus, Ellipta) or 30–90 L/min against R5 DPIs (Handihaler).⁸

Patients were excluded if they were unable to demonstrate proper technique for the In-Check™ DIAL device (Clement Clarke International Ltd., Harlow, UK),⁸ had neuromuscular disease associated with weakness, were unable to achieve the minimum PIF for the prescribed DPI(s) at the screening/enrollment visit (<30 L/min for Handihaler and <60 L/min for Ellipta), had any condition that, in the investigator's opinion, would compromise their ability to participate in the study, or had pneumothorax within the past 4 weeks.

Study procedures

For the primary endpoint, pre- and post-BD spirometry was performed, along with PIF measurements using a handheld pneumotach (Vitalograph Pneumotrac™; Morgan Scientific)²¹ and the In-Check DIAL device, respectively. BDR testing involved baseline spirometry (pre-BD) and measurement with the In-Check DIAL device. Both pre- and post-BD testing by spirometry and the In-Check DIAL device were done at the same study visit. Patients withheld inhaled medicines on the day of spirometry.

Patients inhaled four puffs (360 μg) of albuterol at 1-minute intervals using an MDI (Ventolin^®; GlaxoSmithKline) with a non-static spacer. After a 15-to-20–minute interval, a second forced expiratory maneuver (post-BD) using the spirometer was performed to assess changes in FEV₁ and FVC.^19,22 The FEV₁/FVC ratio was calculated to determine airflow obstruction.^18,23

For both pre- and post-BD testing with the In-Check DIAL device, patients were instructed to prepare for PIF measurements based on previously published recommendations (by “breathing out slowly and fully” before commencing the inhalation maneuver).²⁰ PIF measurements were taken in triplicate, with the highest single value recorded.

The In-Check DIAL device was set according to the manufacturer's recommendations using the resistance of the inhaler(s) that the patients were using at home (R2, for patients who were using R2 resistance; R5, for patients who were using R5; or both, for patients who were using both R2 and R5 inhalers). Patients were seated during spirometry measurements, and subgroup analysis examined pre- and post-albuterol changes in relation to inhaler resistance and sex.

Statistical analysis

This exploratory analysis did not involve formal power calculations. The variables examined included demographics, clinical variables, and patient-reported outcomes (CAT and modified Medical Research Council scores). Baseline characteristics were stratified by inhaler device type at enrollment, but no statistical analyses were performed due to the non-preassigned groups. Correlations between changes in FEV₁ (by spirometry) and PIF (by the In-Check DIAL) were assessed. Subgroup analyses examined bronchodilation change in relation to inhaler resistance and sex. The results were calculated as median (interquartile range [IQR]) or n (%), with the use of the median accounting for outliers or skewed data.

The distribution of PIF data was visualized using box-and-whisker and scatter plots. The Pearson correlation coefficient (r) values were calculated for FEV₁ and PIF measurements. All analyses were independently completed using Stata version 16.1 (College Station, Texas, USA). To minimize selection bias, all potentially eligible participants identified during the screening were invited to participate.

Results

Overall results

Overall, 63 patients with COPD provided acute BD data employing the In-Check DIAL device (Supplementary Fig. S1). The median age was 64.8 years, 85.7% were non-Hispanic White, 33.3% were current smokers, 57.1% were female, and the median CAT score was 21.0 (Table 1). Overall, 69.8% of patients in the cohort were given an R2 DPI and 30.2% were given an R5 DPI.

Table 1.

Baseline Demographic and Clinical Characteristics

Variable, median (IQR) or n (%)	Overall (N = 63)
Age, years	64.8 (58.0–71.6)
Race, non-Hispanic White	54 (85.7)
Race, Black or African American	9 (14.3)
Sex, female	36 (57.1)
Sex, male	27 (42.9)
Currently smoking	21 (33.3)
Regular smokers	40.0 (35.0–46.0)
Pack-years smoked	50.0 (30.0–82.5)
CAT score	21.0 (17.0–27.0)
mMRC score	3.0 (2.0–4.0)
Device resistance
Low-to-medium (R2)	44 (69.8)
High (R5)	19 (30.2)

CAT, COPD Assessment Test; DPI, dry powder inhaler; IQR, interquartile range; mMRC, modified Medical Research Council; R2, low-to-medium–resistance DPI; R5, high-resistance DPI.

Pulmonary function characteristics

The primary endpoint measurements of pre- and post-BD values represented as median (IQR) are as follows: In-Check DIAL PIF (L/min) 70.0 (55.0–80.0) versus 75.0 (62.0–86.0); spirometry PIF (L/min) 176.7 (142.2–225.6) versus 173.4 (134.4–217.8); FEV₁ absolute (L) 1.1 (0.9–1.5) versus 1.2 (0.9–1.5); and % predicted FEV₁ 46.0 (32.0–53.0) versus 49.5 (36.0–56.7).

With albuterol, 57.1% had a PIF BD change >5.0%, whereas 49.2% had a change >10.0%, measured by the In-Check DIAL device. Similarly, 55.6% had an FEV₁ BD change >5.0% and 28.6% had a percent FEV₁ BD change >10.0% with albuterol. In total, 65.7% (n = 23/35) had an FEV₁ >5% and 60.0% (n = 21/35) had an FEV₁ >10%. The FEV₁/FVC ratios pre- and post-BD were similar (0.5) (Table 2). A total of 12.7% (n = 8/63) demonstrated FEV₁ BDR based on the 2005 ATS/ERS criteria (absolute change ≥0.2 L and % change ≥12%),²² whereas 3.2% (n = 2/63) demonstrated FEV₁ BDR based on the 2021 ATS/ERS criteria.¹⁹

Correlation of pre- and post-BD PIF and FEV₁

The scatterplots of the 63 patients revealed weak correlations between pre- and post-BD absolute PIF and absolute FEV₁ and between pre- and post-BD % PIF and % FEV₁. The correlations observed were r = 0.28 (p = 0.02) for absolute PIF and absolute FEV₁ and r = 0.21 (p = 0.11) for % PIF and % FEV₁ (Fig. 1A, B).

FIG. 1.

Correlation between PIF measured by the In-Check™ DIAL and spirometric FEV₁ pre- and post-BD. The relationship between PIF BD change and FEV₁ BD in patients with COPD (N = 63) is shown as scatterplots. (A) Absolute PIF BD change (L/min) and (B) % PIF BD change. BD, bronchodilator; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in one second; PIF, peak inspiratory flow.

Baseline pre- and post-BD PIF

For the secondary endpoints, the baseline pre- and post-BD PIF measured by the In-Check DIAL device are expressed as overall (n = 63; Fig. 2A) or stratified by inhaler resistance (Fig. 2B) and sex (Fig. 2C and Table 3). The median pre-BD PIF (L/min) compared with post-BD PIF (L/min) was 70.0 versus 75.0 (overall, n = 63), 75.5 versus 83.5 for R2 compared with 45.0 versus 52.0 for R5, and 74.0 versus 83.0 for males compared with 65.5 versus 70.0 for females.

Table 2.

Pulmonary Function Characteristics

Variable, median (IQR) or n (%)	Overall (N = 63)
Variable, median (IQR) or n (%)	Pre-BD	Post-BD
FEV₁/FVC ratio	0.5 (0.4–0.6)	0.5 (0.5–0.6)
FEV₁
Absolute (L)	1.1 (0.9–1.5)	1.2 (0.9–1.5)
% Predicted	46.0 (32.0–53.0)	49.5 (36.0–56.7)
FVC
Absolute (L)	2.3 (1.9–2.8)	2.3 (2.0–2.9)
% Predicted	66.0 (57.0–76.9)	68.0 (61.0–84.1)
FEV₁ BDR^a	—	8 (12.7)
FEV₁ BDR^b	—	2 (3.2)
Spirometry PIF (L/min)	176.7 (142.2–225.6)	173.4 (134.4–217.8)
In-Check™ DIAL PIF (L/min)	70.0 (55.0–80.0)	75.0 (62.0–86.0)

Data were missing for spirometry testing due to the impact of the COVID-19 pandemic. Data missing (n) include pre-BD PIF (spirometry, n = 9); post-BD PIF (spirometry, n = 10).

BDR defined as an increase in FEV₁ or FVC of ≥0.2 L and ≥12% relative to pre-BD values.¹⁷

BDR defined as a change of >10% relative to the predicted value in FEV₁ (or FVC) is considered a significant BDR response.¹⁴

BD, bronchodilator; BDR, bronchodilator responsiveness; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; PIF, peak inspiratory flow.

FIG. 2.

Distributional (box-and-whisker) plots of baseline pre- and post-BD PIF measured by the In-Check DIAL. The lower and upper lines (whiskers) indicate each group's smallest and largest baseline pre- and post-BD PIF for (A) overall (N = 63), (B) inhaler resistance, and (C) sex. The horizontal bar inside the box represents the median PIF for each group. DPI, dry powder inhaler; R2, low-to-medium–resistance DPI; R5, high-resistance DPI.

Table 3.

Pre-BD PIF and Post-BD PIF for Overall Analytical Cohort, Inhaler Resistance, and Sex Measured by the In-Check DIAL

Parameter, median (IQR)	Pre-BD PIF (L/min)	Post-BD PIF (L/min)
Overall, N = 63	70.0 (55.0–80.0)	75.0 (62.0–86.0)
R2	75.5 (68.0–85.0)	83.5 (73.5–90.0)
R5	45.0 (44.0–54.0)	52.0 (48.0–62.0)
Male	74.0 (64.0–85.0)	83.0 (72.0–93.0)
Female	65.5 (49.0–76.0)	70.0 (56.0–82.0)

BD change in PIF from baseline

In the analytical cohort, employing the In-Check DIAL device, the median absolute PIF change from baseline was 5.0 L/min, whereas the % PIF change was 8.9% (Fig. 3 and Table 4). R2 showed an absolute PIF BD change of 7.0 L/min versus 2.0 L/min for R5 and a % PIF BD change of 10.7% versus 4.4%, respectively. The median absolute and % PIF increase in pre- and post-BD was 8.0 L/min and 10.6%, respectively, in males and 3.0 L/min and 4.3% in females.

FIG. 3.

Distributional (box-and-whisker) plots of BD change from baseline in PIF measured by the In-Check DIAL (absolute and %). The lower and upper lines (whiskers) indicate each group's smallest and largest change from baseline in PIF (absolute and %) for (A) overall (N = 63), (B) inhaler resistance, and (C) sex. The horizontal bar inside the box represents the median PIF for each group. The dot denotes an outlier.

Table 4.

Absolute PIF and % PIF Change from Baseline Measured by the In-Check DIAL

Variables, median (IQR)	Absolute PIF change (L/min)	% PIF change from baseline
All, N = 63	5.0 (1.0–12.0)	8.9 (1.1–18.2)
R2, n = 44	7.0 (1.5–12.0)^a	10.7 (1.9–16.7)^b
R5, n = 19	2.0 (0.0–8.0)	4.4 (0.0–19.1)
Male, n = 27	8.0 (2.0–15.0)	10.6 (2.6–22.0)
Female, n = 36	3.0 (0.0–9.5)	4.3 (0.0–16.7)

Difference in absolute PIF change by inhaler type (R2 vs. R5), p = 0.24.

Difference in % change in PIF by inhaler type (R2 vs. R5), p = 0.80.

Discussion

In this observational study of patients with COPD with a low prevalence of BDR based on spirometry, we found that PIF increased by more than 10% in many patients as a consequence of acute bronchodilation when measured with a portable inspiratory device. PIF is responsive to BDs; however, the exact magnitude of change in clinically relevant PIF remains unknown.

Recently, PIF has been increasingly recognized as a physiological measure that may have clinical applications in COPD, such as identifying high-risk patients⁷ or monitoring the effective use of inhalers.^7,16 The increase in PIF with BD was less evident using a high-resistance setting with the In-Check DIAL device. Notably, males were more likely to show BDR as measured by PIF than females.

BDR^19,22 is prevalent in most COPD patients¹⁸ and can be influenced by factors such as patient characteristics, BD class selection, and dosage/timing.²⁴ Previous studies have examined BDR in FEV₁ and FVC,^18,24 suboptimal PIF (sPIF) and COPD,^6,25–28 and PIF in hospitalized patients with COPD.^2,25 Notably, our study is the first to investigate the significance of BDR, defined by a post-BD change in PIF as a measure reflecting the change in IF in patients with stable COPD.

Our results showed that following albuterol administration, 57.1% of patients had a PIF BD change >5.0%, whereas 49.2% had a change >10.0%. Overall, 65.7% of patients showed an FEV₁ increase >5% and 60.0% had an FEV₁ increase >10%. According to the 2005 ATS/ERS criteria,²² 12.7% of patients demonstrated FEV₁ BDR, whereas 3.1% showed FEV₁ BDR based on the 2021 ATS/ERS criteria.¹⁹ These findings contribute to the existing evidence,^29,30 supporting the evaluation of lung-volume responses and reproducibility of BDR to bronchodilation in patients with COPD.

Additionally, our study found a weak correlation between the change in PIF measurements obtained using the In-Check DIAL device and the change in FEV₁ following BD administration. It is important to note that FEV₁ is a measure of lung function that reflects the amount of air a patient can forcefully exhale for one second after taking a deep breath,³¹ whereas PIF is an inspiratory effort. The weak correlation suggests that improving PIF does not necessarily correlate with improved lung function.

Nonetheless, it is important to assess pulmonary function tests accurately to capture the full complexity of COPD,^19,31,32 as FEV₁/FVC ratio, FEV₁, and FVC alone may not fully uncover the intricacies of the disease. Further, % predicted FEV₁ or other relevant lung parameters can be employed as quantifiable measures of pulmonary obstruction. In contrast to when using the In-Check DIAL device, the bronchodilatory effect with inhaled albuterol on PIF measured by spirometry was unreliable in our study.

Correlation between PIF measured by spirometry and the In-Check DIAL device in stable COPD has been inconsistent.^27,33 The emphasis on the expiratory loop in spirometry contrasts with the sole emphasis on inhalation measurement in PIF meters, likely affecting the reliability of the inspiratory measurements. Consequently, BDR was not observed with PIF when measured by spirometry in our study.

In 10 patients with chronic bronchial asthma experiencing breathing difficulties, Wells observed elevated airway resistance resembling emphysema's check-valve mechanism, emphasizing the importance of interventions to restore respiratory function by overcoming airway resistance.³⁴ Therefore, the bronchodilatory effects of medications, such as albuterol, may contribute to a reduction in hyperinflation and improvement in inspiratory pressure (IP), subsequently alleviating breathlessness.³⁵ Improved inspiratory effort and flow enhance inhalation, leading to favorable outcomes for patients with COPD.

It is crucial to consider factors beyond FEV₁ alone when selecting inhalers, and PIF is an important consideration in this respect, but other factors may also help predict response.^6,7,36–39 According to Janssens et al., maximum IP, spirometric PIF, and inspiratory capacity (IC) are lung functions that can predict PIF across different DPIs, whereas FEV₁, an indicator of illness severity, does not correlate with maximal IF.³⁸ In our study, the post-BD FEV₁/FVC ratio was 0.5, meeting the criterion for a COPD diagnosis based on an FEV₁/FVC ratio <0.70.¹

However, it is important to note that the pathophysiological changes associated with COPD occur before this criterion is met.³² FVC can detect early small airway disease and is reduced when <60% of the % predicted value, serving as a useful spirometric surrogate marker.³²

Additionally, analyzing the pattern of PIF BDR based on changes in FEV₁ and FVC enhances its clinical significance.¹⁸ While this study did not measure lung volumes to assess directional hyperinflation changes, BDR FVC can be considered an indicator of emphysema and small airway disease.^18,40 Previously, BDR was primarily defined using FEV₁, an expiratory maneuver.²²

However, in this study, we investigated the effects of BDR on an inspiratory maneuver. Interestingly, we observed no correlation between PIF and FEV₁, which aligns with several other studies, indicating little or no relationship between PIF and FEV₁.^7,27,37,39

In a study involving 213 patients, it was found that patients with a PIF <60 L/min using Diskus inhaler had significantly lower % predicted IC compared with those with a PIF >60 L/min.³⁶ Reduced IC suggests the presence of lung hyperinflation, insufficient PIF generation, and an increased risk of respiratory mortality.^17,32 Therefore, nebulized BD therapy is recommended for patients with low sPIF using a specific DPI.^36,41

Further, regular assessment of PIF is advised in the outpatient settings and before discharge, following an exacerbation, particularly when a BD DPI is prescribed.³ If the patient's PIF is ≥60 L/min, DPIs can be used effectively using the correct inhalation technique. However, if the PIF is <60 L/min, alternative delivery systems, such as pMDI, soft mist inhalers, or nebulized therapy, should be considered.³ Consequently, when uncertainty exists regarding a patient's ability to produce sufficient inspiration, using the In-Check DIAL device for measurement is advisable³⁹ to ensure proper medication inhalation and to maximize therapeutic benefits.

Our study found that R5 DPI demonstrated a lower PIF and minimal change in BDR. Interestingly, there is an inconsistent correlation between PIF (measured against resistance) and FEV₁ and % predicted FEV₁.⁶ A cross-sectional study undertaken in nursing homes in Europe showed that the In-Check DIAL enables testing of every DPI device based on its internal resistance, yielding reproducible measurements at different times of the day.⁴² These findings highlight the potential impact of DPI resistance settings on BDR, underscoring the importance for physicians to consider the DPI resistance setting when prescribing inhaler devices for patients with respiratory diseases.³

In this study, the overall median absolute PIF BD change was 5.0 L/min measured by the In-Check DIAL device (Table 4). Males exhibited a larger BD change than females, indicating the effectiveness of bronchodilation and responsiveness of PIF was more substantially increased in males. Previous studies have correlated variable demographics, such as age and female sex, with PIF.³⁷ Female sex and lung hyperinflation have been shown to reduce inspiratory muscle strength.³

A prospective observational study in the United States revealed that patients with lower PIF rates compared with patients with normal rates had a higher proportion of women (61.2% vs. 42.4%, p = 0.014).¹⁰ Interestingly, a U.S. single-center, cross-sectional, exploratory study showed that one in five ambulatory patients with COPD had an sPIF (measured with the In-Check DIAL), and most were females with shorter heights.²⁷

This suggests that females with COPD may have reduced inspiratory muscle strength, leading to lower PIF values. In line with these findings, our study demonstrated that females had lower pre-BD PIF and a lesser increase in PIF following bronchodilation, highlighting the importance of personalized inhaler selection.

The recommendations from this study are practical and easy to implement, such as the administration of acute BD before DPIs with proper guidance. While the median increase in PIF was 5.0 L/min by the In-Check DIAL device, nearly 50% reported an increase in PIF >10% with four puffs of albuterol. To gain a comprehensive understanding of the various determinants influencing pulmonary drug delivery through DPIs, it is crucial to address as many modifiable factors as possible. Interestingly, electronic monitoring devices can now assess the vital aspects of inhaler technique, including whether an adequate PIF is achieved by the patient when using a DPI.^43,44

In a randomized study in 391 patients with asthma (≥13 years old) using a digital DPI (Digihaler^®; Teva) for over 24 weeks, low PIF was the most common reason for interactions between the patient and health care professional, when using digitally collected data.⁴⁵ The Digihaler platform informs the patient and the health care professional whether a minimum PIF is achieved with each inhalation. This and other feedback such as medication adherence led to better asthma control in the study.⁴⁵

The limitations of our study include its single-center design and sample size, which may affect the generalizability of the findings. As an observational study, it may be prone to bias. Additionally, the timing of PIF measurements was influenced by the severe acute respiratory syndrome coronavirus 2 pandemic in early 2020. Therefore, PIF values obtained in this supervised study may not reflect real-world settings.

Future research on the BDR of PIF measurements should focus on the extent that aerosol drug delivery by a DPI is improved when given after a short-acting BD, and whether increases in PIF with albuterol predict a clinical response to a maintenance BD in COPD patients.

Conclusions

In stable COPD, acute BD administration increased PIF measured by the In-Check DIAL device, but the minimal clinically significant increase in PIF remains unknown. Reduced lung function, sex, and physical limitations can contribute to reduced PIF and impact DPI medication effectiveness. Physicians may consider prescribing acute BDs before using DPIs to improve PIF and pulmonary medication deposition; however, further research is warranted to explore the impact of PIF on DPI medication delivery.

Footnotes

Acknowledgments

This study was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the article for medical and scientific accuracy and intellectual property considerations.

The authors received no direct compensation for the development of this article. Writing, editorial support, and formatting assistance for this article were provided by Reham M. Milhem, PhD, of Cactus Life Sciences (part of Cactus Communications), which was contracted and compensated by BIPI for these services.

Authors' Contributions

Conceptualization and study design: R.A.P., A.S., A.G.H., and M.B.D. Data acquisition: R.A.P., A.G.H., and M.B.D. Data analysis and interpretation: A.S., V.B., and M.B.D. Reviewing and editing the article: R.A.P., A.S., A.G.H., V.B., and M.B.D. M.B.D. conducted and takes sole responsibility for data analyses.

Author Disclosure Statement

R.A.P. reports research grants from AstraZeneca, BIPI, and Teva. A.G.H. has no competing interests to disclose. A.S. and V.B. are employees of BIPI. M.B.D. reports grants from BIPI to conduct this study and provided consulting services for BIPI. M.B.D. reports research grants from the National Institutes of Health, Department of Defense, Patient-Centered Outcomes Research Institute, American Lung Association, Midmark Corporation, and Teva unrelated to this work. M.B.D. reports personal consulting fees from BIPI, GlaxoSmithKline, AstraZeneca, Teva, Midmark, Verona, Chiesi, and Polarean, Inc., unrelated to this work.

Funding Information

A grant from BIPI supported this research (CTMS 0352-2137). BIPI was given the opportunity to review the article for medical and scientific accuracy as it relates to BIPI substances as well as intellectual property considerations.

Supplementary Material

Reviewed by:

Michael Hindle

Arsu Ari

References

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Supplementary Material

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Changes in Peak Inspiratory Flow After Acute Bronchodilation: An Observational Study of Patients with Stable Chronic Obstructive Pulmonary Disease

Abstract

Introduction:

Materials and Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Study design

Study population

Study procedures

Statistical analysis

Results

Overall results

Pulmonary function characteristics

Correlation of pre- and post-BD PIF and FEV1

Baseline pre- and post-BD PIF

BD change in PIF from baseline

Discussion

Conclusions

Footnotes

Acknowledgments

Authors' Contributions

Author Disclosure Statement

Funding Information

Supplementary Material

References

Supplementary Material

Correlation of pre- and post-BD PIF and FEV₁