Optimizing inhalation therapy in the aspect of peak inhalation flow rate in patients with chronic obstructive pulmonary disease or asthma

Chronic respiratory diseases, especially Chronic obstructive pulmonary disease (COPD) and asthma, are common diseases worldwide with leading mortality and morbidity. In China, the prevalence of COPD in patients over 40 years old was 8.2–13.7% [1, 2]. COPD has accounted for 1.6% of all hospital admissions and ranked as the fourth leading cause of death in urban areas and the third leading cause of death in rural areas worldwide [3]. COPD has been a heavy burden for China, with a direct medical cost of $72 to $3565 per capita per year accounting for 40% of the average family's total income [4]. In the recent epidemiological studies, the overall prevalence of asthma in China ranged from 1.2 to 5.8%, while 4.2% among adults [5, 6].

Inhalation therapies, including inhaled corticosteroid (ICS), long-acting β2 agonists (LABA) and long-acting muscarinic antagonists (LAMA), play an important role for the treatment and management of both COPD and asthma [7]. Inhalers typically used for inhalation therapy are sorted into three types based on their respective technical characteristics and particle properties: pressurized metered dose inhaler (pMDI), dry powder inhalers (DPIs), soft mist inhalers (SMI). pMDIs do not require the patients’ peak inhalation flow rate (PIFR) to reach a certain value, but drug delivery using pMDIs is highly dependent on the patient’s inhaler technique [8]. Failure to coordinate or synchronize actuation with inhalation leading to suboptimal lung deposition are commonplace reported in previous studies [9]. In comparison, DPIs are essentially breath-actuated and easier to use correctly than pMDIs, but demand patients to generate a sufficient inspiratory flow to release the powder and break up the powder packets into respirable particles (less than 5 μm in diameter) [10].

Recently, PIFR has been believed as a measure to assess patients' capacity to use DPIs [11]. DPIs approved for treatment of COPD and Asthma include the HandiHaler, Turbuhaler, Aerolizer, Accuhaler/Diskus, Breezhaler, Genuair/Pressair, etc. The recommended technique for patients when using DPIs is ‘a fast and hard inhalation’. Due to the difference in the internal resistance of devices, the level of resistance that the patient needs to overcome when using different DPIs varies. For example, using DPIs with high resistance like Turbuhaler and HandiHaler require more inspiratory effort than using those with low resistance like Breezhaler. Patients using DPIs need to achieve a minimum inhalation rate for the effective clinical response or ideally an optimal rate for the best response. Given previous studies, it is generally considered that PIFR less than 30 L/min is insufficient for the use of DPIs [12]. PIFR of at least 60L/min achieved by patients can bring about optimal drug delivery through DPIs [13]. Unlike DPIs, the technical essential for patients when using pMDI is ‘a slow and deep inhalation’, which requires that the patient's PIFR should be less than 90 L/min [14]. However, observational studies demonstrate that 19% of patients with stable COPD or asthma [15] and 32% to 47% of in-patients prior to discharge after recovering from exacerbation suffered a suboptimal PIFR (less than 60L/min) [16]. Moreover, the PIFRs of 12% of elder Turbuhaler users were even lower than the minimum effective rate (30 L/min) [17]. If patients' inspiratory flow rate does not match DPIs, the insufficient PIFR associating with the dose of inhaled drugs poorly deposited in lung will result in unsatisfied efficacy and potentially poor prognosis [18, 19]. Overall, PIFR is an important consideration for physicians to choose an appropriate inhaler for patients.

Appropriate technique for the usage of inhalers is quite important for the efficacy of inhalation therapy that improper technique is significantly associated with uncontrolled symptoms and increased exacerbation rate [20]. For patients using DPIs and pMDIs, the most critical and common technique errors are inappropriate inspiratory maneuver and poorly synchronized hand actuation with inhalation, respectively [21]. Several reports have revealed that up to 70%-80% of patients made at least 1 inhalation technique error when using DPIs, and 86%-87% of patients when using pMDIs [22, 23]. Especially, patients using Turbuhaler are most likely to make mistakes [24]. Therefore, enhancing patients’ inhaler technique through teaching and training may contribute to improving prognosis and decreasing medical expenditure.

In the current study, we aimed to investigate the PIFRs of patients with COPD or asthma, factors that affect PIFRs and the effect of inhaler technique training on optimizing patients’ PIFRs before inhalation therapy. Through this study, the optimized inhalation therapy based on PIFR should be guided both in selection of the most acceptable inhaler for patients and in training to improve inhaler technique.

Different inhalers have different requirements for the patient's inspiratory flow rate and technique [26]. Although the types of inhalers available to doctors and patients are increasing day by day, there are still many patients whose PIFR does not match the requirements of the inhaler or the inhaler technique is not qualified, resulting in suboptimal efficacy of inhalation therapy [27, 28]. In this prospective, self-control, single-center study, the number of patients with very severe COPD (GOLD IV, defined as FEV₁% < 30%) is relatively small (12 patients, 14.5%) since the patients we enrolled were all outpatients. Though after training, 39.5% of patients were not yet able to achieve the optimal PIFR (60L/min), which showed that there were still quite a few patients with a suboptimal inspiratory flow rate even in patients with mild, moderate or severe COPD (GOLD I–III).

In this study, in addition to routine instructional video and oral guidance by physicians, we additionally emphasized the application of In-Check DIAL® in technique training. Our study has shown that 10.8% of patients using DPI could not achieve the minimum PIFR (30L/min) and 55.9% of patients could not achieve the optimal PIFR (60L/min) before technical training. After training, almost no patients had a PIFR less than 30L/min, and the number of patients who did not reach the optimal flow rate was significantly reduced, which revealed that technique training helped to significantly increased both the value of PIFR and the proportion of patients that reached the minimum and optimal flow rate. Our attempt to train patients with In-Check DIAL® truly contributed to improving PIFR of patients with COPD or asthma. Moreover, the improvement of PIFR in COPD patients before and after training was more significant than that of asthmatic patients. Therefore, we considered that COPD patients need more training, probably because asthma patients were younger and stronger in learning ability than COPD patients.

We have investigated the distribution of PIFRs in patients with different clinical conditions in this study. By comparing PIFR (including PIFR₀, PIFR_AT and PIFR_BT) in new-diagnosed (indicating no effective treatment had ever be used) vs. follow-up patients and patients in exacerbation vs. stable stage, we found that PIFR of ND/FU group or AE/Stable group showed a significant difference. It meant that compared with follow-up patients, newly-diagnosed patients who were given inhalation therapy for the first time benefited more from inhaler technique training in improving the ability of using DPIs; and compared with AE patients, patients in the stable phase benefited more in improving PIFR.

From the distribution of PIFR_AT and PIFR_BT, it is not difficult to find that among all the groups before teaching, ND group had the largest proportion of PIFR_BT less than 30 L/min (13.9%) and the smallest proportion of PIFR_BT greater than or equal to 60 L/min (26.4%), but FU group had the largest proportion of PIFR_BT greater than or equal to 60 L/min (54.5%). These data suggest that newly diagnosed patients should strengthen knowledge education and inhaler technique training, and pMDIs may be prescribed for some patients with suboptimal PIFR (DPIs can be prescribed after improvement).

Among all the groups after teaching, AE group had the least proportion of PIFR_AT greater than or equal to 60 L/min (41.2%), which is significantly lower than that of the stable group (68.3%). In the AE group, the improvement in PIFR before and after training (P > 0.050) did not reach statistical significance, indicating that many AE patients had poor inhalation ability and the benefits of training for AE patients were limited. It can be found that when the influence of technical factors on PIFR is excluded, AE patients had a higher suboptimal rate and a worse ability to use DPIs than stable patients, but physicians kept giving DPIs to them (AE patients used 1.00 DPIs per capita). Previous researches have shown similar conclusions that acute exacerbations were associated with decrease in PIFR [27, 29]. For example, Palen et al. found that 50% of patients with an exacerbation of asthma or COPD were unable to generate optimal PIFR using Turbuhaler (compared with 5% of those without AE) [30]. All these data have proved that more AE patients were suitable to be prescribed SMIs or pMDIs rather than DPIs.

According to the study by Duarte et al., lung function measurements demonstrated a significant lower FEV₁, total lung capacity (TLC), inspiratory capacity (IC) and a significant greater RV/TLC in the suboptimal PIFR group compared to the optimal PIFR group [31]. By contrast, Ghosh et al. demonstrated that the only factor found to be consistently associated with a lower PIFR was female gender, but there was a lack of consistent correlation between PIFR and FEV₁ or FEV₁% predicted or FVC or CAT score [26, 32]. In fact, the factors affecting PIFR are still controversial. In this study, we found a weak positive correlation between PIFR of outpatients with FEV₁, PEF and IC (r = 0.199, 0.218, and 0.284), and a weak negative correlation with mMRC score (r = -0.200). However, our attempt to construct a qualified prediction model for PIFR based on these factors was a failure. At this stage, it is still necessary to measure PIFR by In-Check DIAL® to guide inhaler choice.

In addition, a slow and deep inhalation is required when using pMDIs, and a PIFR greater than 90L/min is considered too fast. Some studies have proven the necessity to educate patients regarding correct pMDI technique [33, 34]. Our results showed that training reduced the PIFR value of patients, but it was not statistically significant, which implied that technique training had potential impact for patients to use pMDIs correctly in the aspect of optimal PIFR.

In general, a considerable number of outpatients with COPD or asthma were not able to achieve the optimal PIFRs for using DPIs. Inhaler education including training using In-Check DIAL® played an important role in improving patients’ PIFRs and we recommend that all patients who are prescribed inhalers should have their abilities evaluated and techniques trained. PIFR was associated with patients’ FEV₁, PEF, IC and mMRC, but the correlation was not strong enough to indicate optimal PIFR to use specific DPIs. Besides, patients with AECOPD or asthma attack generally had suboptimal PIFRs and should be prescribed DPIs with caution.