Identifying critical inhalation technique errors in Dry Powder Inhaler use in patients with COPD based on the association with health status and exacerbations: findings from the multi-country cross-sectional observational PIFotal study.

BACKGROUND: Correct inhaler use depends on a complex interplay of factors, including device preparation and generating sufficient inspiratory flow. It is currently unknown which inhalation technique errors can be considered critical in Chronic Obstructive Pulmonary Disease (COPD) patients on Dry Powder Inhaler (DPI) maintenance therapy. OBJECTIVE: To investigate the association between inhalation technique errors and health status or exacerbations in patients with COPD. Additionally, the association between the number of errors and COPD outcomes was determined. METHODS: The PIFotal study is a cross-sectional multi-country observational study in a primary care setting, including 1434 COPD patients aged ≥ 40 years (50.1% female; mean age 69.2 yrs) using a DPI for their maintenance therapy. Inhalation technique was video recorded and scored by two independent researchers using inhaler-specific checklists. Health status was assessed with two questionnaires; the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT). The number of moderate and severe exacerbations in the past 12 months was recorded. Critical errors were identified based on their association with health status or exacerbations through multi-level prediction models adjusted for identified confounding. RESULTS: Errors in inhalation technique steps 'Breathe in', 'Hold breath', and 'Breathe out calmly after inhalation' were significantly associated with poorer CCQ and CAT outcomes and thus deemed critical. None of the errors were significantly associated with moderate exacerbations. Patients with errors 'Preparation', 'Hold inhaler in correct position during inhalation', and 'Breathe in' had significantly more severe exacerbations, and therefore these errors were also deemed critical. 81.3% of patients with COPD made at least one critical error. Specific combinations of errors were associated with worse outcomes. The more inhalation technique errors identified, the poorer the health status and the higher the exacerbation rate. CONCLUSION: In this study, we identified multiple critical inhalation technique errors in COPD patients using DPIs each associated with poorer outcomes. Explorative analysis revealed that specific combinations of errors may be of clinical relevance, especially those related to the inhalation manoeuvre. COPD outcomes worsened with increasing error count. These results warrant further prospective longitudinal studies to establish the effect of correcting these errors on COPD control. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04532853 (31/08/2020).

Clinical recommendations for dry powder inhaler use in the management of COPD in primary care.

Over 1400 patients using dry powder inhalers (DPIs) to deliver COPD maintenance therapies were recruited across Europe and Australia. Their peak inspiratory flow (PIF) was measured, inhaler technique was observed, and adherence to treatment assessed. From relating the findings with patient health status, and thereby identifying critical errors, key clinical recommendations for primary care clinicians were determined, namely - measure PIF before prescribing a DPI to ensure inhalation manoeuvre ability is well-matched with the device. Some patients could benefit from inhalation training whereas others should have their DPI changed for one better suited to their inspiratory ability or alternatively be prescribed an active device (such as a soft mist inhaler or pressurized metered dose inhaler). Observing the inhalation technique was valuable however this misses suboptimal PIF (approaching one fourth of patients with a satisfactory observed manoeuvre had a suboptimal PIF for their DPI). Assess adherence as deliberate non-adherence can point to a mismatch between a patient and their inhaler (deliberate non-adherence was significantly associated with PIFs below the minimum for the DPI). In-person observation of inhalation technique was found to be inferior to video rating based on device-specific checklists. Where video assessments are not possible, observation training for healthcare professionals would therefore be valuable particularly to improve the ability to identify the critical errors associated with health status namely 'teeth and lips sealed around mouthpiece', 'breathe in' and 'breathing out calmly after inhalation'. However, it is recommended that observation alone should not replace PIF measurement in the DPI selection process.Trial registration: https://clinicaltrials.gov/ct2/show/NCT04532853 .

Suboptimal Peak Inspiratory Flow and Critical Inhalation Errors are Associated with Higher COPD-Related Healthcare Costs.

Purpose: To assess the relationship between suboptimal Peak Inspiratory Flow (sPIF), inhalation technique errors, and non-adherence, with Healthcare Resource Utilisation (HCRU) in Chronic Obstructive Pulmonary Disease (COPD) patients receiving maintenance therapy via a Dry Powder Inhaler (DPI). Patients and methods: The cross-sectional, multi-country PIFotal study included 1434 COPD patients (≥40 years) using a DPI for maintenance therapy. PIF was measured with the In-Check DIAL G16, and sPIF was defined as a typical PIF lower than required for the device. Inhalation technique was assessed by standardised evaluation of video recordings and grouped into 10 steps. Patients completed the "Test of Adherence to Inhalers" questionnaire. HCRU was operationalised as COPD-related costs for primary healthcare, secondary healthcare, medication, and total COPD-related costs in a 1-year period. Results: Participants with sPIF had higher medication costs compared with those with optimal PIF (cost ratio [CR]: 1.07, 95% CI [1.01, 1.14]). Multiple inhalation technique errors were associated with increased HCRU. Specifically, "insufficient inspiratory effort" with higher secondary healthcare costs (CR: 2.20, 95% CI [1.37, 3.54]) and higher total COPD-related costs (CR: 1.16, 95% CI 1.03-1.31). "no breath-hold following the inhalation manoeuvre (<6 s)" with higher medication costs (CR: 1.08, 95% CI [1.02, 1.15]) and total COPD-related costs (CR 1.17, 95% CI [1.07, 1.28]), and "not breathing out calmly after inhalation" with higher medication costs (CR: 1.19, 95% CI [1.04, 1.37]). Non-adherence was not significantly associated with HCRU. Conclusion: sPIF and inhalation technique errors were associated with higher COPD-related healthcare utilisation and costs in COPD patients on DPI maintenance therapy.

Factors associated with health status and exacerbations in COPD maintenance therapy with dry powder inhalers.

The study aimed to determine the associations of Peak Inspiratory Flow (PIF), inhalation technique and adherence with health status and exacerbations in participants with COPD using DPI maintenance therapy. This cross-sectional multi-country observational real-world study included COPD participants aged ≥40 years using a DPI for maintenance therapy. PIF was measured three times with the In-Check DIAL G16: (1) typical PIF at resistance of participant's inhaler, (2) maximal PIF at resistance of participant's inhaler, (3) maximal PIF at low resistance. Suboptimal PIF (sPIF) was defined as PIF lower than required for the device. Participants completed questionnaires on health status (Clinical COPD Questionnaire (CCQ)), adherence (Test of Adherence to Inhalers (TAI)) and exacerbations. Inhalation technique was assessed by standardised evaluation of video recordings. Complete data were available from 1434 participants (50.1% female, mean age 69.2 years). GOLD stage was available for 801 participants: GOLD stage I (23.6%), II (54.9%), III (17.4%) and IV (4.1%)). Of all participants, 29% had a sPIF, and 16% were shown able to generate an optimal PIF but failed to do so. sPIF was significantly associated with worse health status (0.226 (95% CI 0.107-0.346), worse units on CCQ; p = 0.001). The errors 'teeth and lips sealed around mouthpiece', 'breathe in', and 'breathe out calmly after inhalation' were related to health status. Adherence was not associated with health status. After correcting for multiple testing, no significant association was found with moderate or severe exacerbations in the last 12 months. To conclude, sPIF is associated with poorer health status. This study demonstrates the importance of PIF assessment in DPI inhalation therapy. Healthcare professionals should consider selecting appropriate inhalers in cases of sPIF.

Perinatal fluoxetine treatment and dams' early life stress history have opposite effects on aggressive behavior while having little impact on sexual behavior of male rat offspring.

RATIONALE: Many depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior. OBJECTIVES: Our aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring. METHODS: Heterozygous serotonin transporter (SERT± ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2-15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT+/+) and reduced (SERT± ) SERT expression were assessed. RESULTS: Perinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT+/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT+/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT± offspring. CONCLUSIONS: Overall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.

Perinatal fluoxetine treatment and dams' early life stress history alter affective behavior in rat offspring depending on serotonin transporter genotype and sex.

Many women diagnosed with a major depression continue or initiate antidepressant treatment during pregnancy. Both maternal stress and selective serotonin inhibitor (SSRI) antidepressant treatment during pregnancy have been associated with changes in offspring behavior, including increased anxiety and depressive-like behavior. Our aim was to investigate the effects of the SSRI fluoxetine (FLX), with and without the presence of a maternal depression, on affective behavior in male and female rat offspring. As reduced serotonin transporter (SERT) availability has been associated with altered behavioral outcome, both offspring with normal (SERT+/+) and reduced (SERT+/-) SERT expression were included. For our animal model of maternal depression, SERT+/- dams exposed to early life stress were used. Perinatal FLX treatment and early life stress in dams (ELSD) had sex- and genotype-specific effects on affective behavior in the offspring. In female offspring, perinatal FLX exposure interacted with SERT genotype to increase anxiety and depressive-like behavior in SERT+/+, but not SERT+/-, females. In male offspring, ELSD reduced anxiety and interacted with SERT genotype to decrease depressive-like behavior in SERT+/-, but not SERT+/+, males. Altogether, SERT+/+ female offspring appear to be more sensitive than SERT+/- females to the effects of perinatal FLX exposure, while SERT+/- male offspring appear more sensitive than SERT+/+ males to the effects of ELSD on affective behavior. Our data suggest a role for offspring SERT genotype and sex in FLX and ELSD-induced effects on affective behavior, thereby contributing to our understanding of the effects of perinatal SSRI treatment on offspring behavior later in life.