The Inhalation Characteristics of Patients When They Use Different Dry Powder Inhalers

Background: The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose. Methods: We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their “real-life” DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (ΔP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver. Results: PIF, ΔP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, ΔP, and ACCEL (p4 L and ΔP >4 kPa. Conclusion: The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation

Dynamics of airflow in a short inhalation

During a rapid inhalation, such as a sniff, the flow in the airways accelerates and decays quickly. The consequences for flow development and convective trans- port of an inhaled gas were investigated in a subject geometry extending from the nose to the bronchi. The progress of flow transition and the advance of an inhaled non-absorbed gas were determined using highly resolved simulations of a sniff 0.5 s long, 1 litre per second peak flow, 364 ml inhaled volume. In the nose, the distribution of airflow evolved through three phases: (i) an initial transient of about 50 ms, roughly the filling time for a nasal volume, (ii) quasi-equilibrium over the majority of the inhalation, and (iii) a terminating phase. Flow transition commenced in the supraglottic region within 20ms, resulting in large- amplitude fluctuations persisting throughout the inhalation; in the nose, fluctuations that arose nearer peak flow were of much reduced intensity and diminished in the flow decay phase. Measures of gas concentration showed non-uniform build-up and wash-out of the inhaled gas in the nose. At the carina, the form of the temporal concentration profile reflected both shear dispersion and airway filling defects owing to recirculation regions.Comment: 15 page

Inhalation characteristics of asthma patients, COPD patients and healthy volunteers with the Spiromax® and Turbuhaler® devices: a randomised, cross-over study.

BACKGROUND: Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF). The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD). The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation. METHODS: This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50). Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device. RESULTS: After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups). After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients. After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler. All patients achieved PIF values of at least 30 L/min after enhanced training. CONCLUSIONS: The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar. The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use. After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery. Enhanced training could be useful, especially in COPD patients

Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure

Air pollution is linked to increased emergency department visits for headache and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that chronic environmental irritant exposure sensitizes the trigeminovascular system response to nasal administration of environmental irritants. Here, we examine whether chronic environmental irritant exposure induces migraine behavioral phenotypes. Male rats were exposed to acrolein, a transient receptor potential channel ankyrin-1 (TRPA1) agonist, or room air by inhalation for 4 days before meningeal blood flow measurements, periorbital cutaneous sensory testing, or other behavioral testing. Touch-induced c-Fos expression in trigeminal nucleus caudalis was compared in animals exposed to room air or acrolein. Spontaneous behavior and olfactory discrimination was examined in open-field testing. Acrolein inhalation exposure produced long-lasting potentiation of blood flow responses to a subsequent TRPA1 agonist and sensitized cutaneous responses to mechanical stimulation. C-Fos expression in response to touch was increased in trigeminal nucleus caudalis in animals exposed to acrolein compared with room air. Spontaneous activity in an open-field and scent preference behavior was different in acrolein-exposed compared with room air-exposed animals. Sumatriptan, an acute migraine treatment blocked acute blood flow changes in response to TRPA1 or transient receptor potential vanilloid receptor-1 agonists. Pretreatment with valproic acid, a prophylactic migraine treatment, attenuated the enhanced blood flow responses observed after acrolein inhalation exposures. Environmental irritant exposure yields an animal model of chronic migraine in which to study mechanisms for enhanced headache susceptibility after chemical exposure

Long-term clearance from small airways in subjects with ciliary dysfunction

The objective of this study was to investigate if long-term clearance from small airways is dependent on normal ciliary function. Six young adults with primary ciliary dyskinesia (PCD) inhaled (111 )Indium labelled Teflon particles of 4.2 μm geometric and 6.2 μm aerodynamic diameter with an extremely slow inhalation flow, 0.05 L/s. The inhalation method deposits particles mainly in the small conducting airways. Lung retention was measured immediately after inhalation and at four occasions up to 21 days after inhalation. Results were compared with data from ten healthy controls. For additional comparison three of the PCD subjects also inhaled the test particles with normal inhalation flow, 0.5 L/s, providing a more central deposition. The lung retention at 24 h in % of lung deposition (Ret(24)) was higher (p < 0.001) in the PCD subjects, 79 % (95% Confidence Interval, 67.6;90.6), compared to 49 % (42.3;55.5) in the healthy controls. There was a significant clearance after 24 h both in the PCD subjects and in the healthy controls with equivalent clearance. The mean Ret(24 )with slow inhalation flow was 73.9 ± 1.9 % compared to 68.9 ± 7.5 % with normal inhalation flow in the three PCD subjects exposed twice. During day 7–21 the three PCD subjects exposed twice cleared 9 % with normal flow, probably representing predominantly alveolar clearance, compared to 19 % with slow inhalation flow, probably representing mainly small airway clearance. This study shows that despite ciliary dysfunction, clearance continues in the small airways beyond 24 h. There are apparently additional clearance mechanisms present in the small airways

Flow and particle deposition using an integrated CFD model of the respiratory system

This paper was presented at the 3rd Micro and Nano Flows Conference (MNF2011), which was held at the Makedonia Palace Hotel, Thessaloniki in Greece. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, Aristotle University of Thessaloniki, University of Thessaly, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute.In the present study a theoretical investigation on flow, particle motion, and deposition in the respiratory system is reported. An integrated computational model of the respiratory system is developed comprised of nine sequential computational blocks corresponding to the nasal cavity, the pharyngo-trachea, and a series of branches of the pulmonary system. Airflow during steady-state inhalation inside the human respiratory system was determined using computational fluid dynamics (CFD) for inlet velocities, vin = 1-20 m/s, corresponding to inhalation flow rates of 9 to 180 L/min, and particle deposition was examined in detail for particle sizes, D=1-20μm. Local deposition efficiencies as well as spatial distribution of deposited particles were found to be strongly dependent on the particle size and volumetric flow rate

Pesticide Flow Analysis to Assess Human Exposure in Greenhouse Flower Production in Colombia

Human exposure assessment tools represent a means for understanding human exposure to pesticides in agricultural activities and managing possible health risks. This paper presents a pesticide flow analysis modeling approach developed to assess human exposure to pesticide use in greenhouse flower crops in Colombia, focusing on dermal and inhalation exposure. This approach is based on the material flow analysis methodology. The transfer coefficients were obtained using the whole body dosimetry method for dermal exposure and the button personal inhalable aerosol sampler for inhalation exposure, using the tracer uranine as a pesticide surrogate. The case study was a greenhouse rose farm in the Bogota Plateau in Colombia. The approach was applied to estimate the exposure to pesticides such as mancozeb, carbendazim, propamocarb hydrochloride, fosetyl, carboxin, thiram, dimethomorph and mandipropamide. We found dermal absorption estimations close to the AOEL reference values for the pesticides carbendazim, mancozeb, thiram and mandipropamide during the study period. In addition, high values of dermal exposure were found on the forearms, hands, chest and legs of study participants, indicating weaknesses in the overlapping areas of the personal protective equipment parts. These results show how the material flow analysis methodology can be applied in the field of human exposure for early recognition of the dispersion of pesticides and support the development of measures to improve operational safety during pesticide management. Furthermore, the model makes it possible to identify the status quo of the health risk faced by workers in the study area

Potential of a cyclone prototype spacer to improve in vitro dry powder delivery

Copyright The Author(s) 2013. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPurpose: Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrierbased DPIs was investigated. Methods: Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30-60 Lmin-1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography. Results: Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89 ± 6.51 % at 30 Lmin-1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08 ± 0.05 μm vs. 3.00 ± 0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates. Conclusion: This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.Peer reviewe

Respiratory analysis system and method

A system is described for monitoring the respiratory process in which the gas flow rate and the frequency of respiration and expiration cycles can be determined on a real time basis. A face mask is provided with one-way inlet and outlet valves where the gas flow is through independent flowmeters and through a mass spectrometer. The opening and closing of a valve operates an electrical switch, and the combination of the two switches produces a low frequency electrical signal of the respiratory inhalation and exhalation cycles. During the time a switch is operated, the corresponsing flowmeter produces electric pulses representative of the flow rate; the electrical pulses being at a higher frequency than that of the breathing cycle and combined with the low frequency signal. The high frequency pulses are supplied to conventional analyzer computer which also receives temperature and pressure inputs and computes mass flow rate and totalized mass flow of gas. From the mass spectrometer, components of the gas are separately computed as to flow rate. The electrical switches cause operation of up-down inputs of a reversible counter. The respective up and down cycles can be individually monitored and combined for various respiratory measurements

Clinical Studies on Reversibility of Pulmonary Airway Dysfunctions in Asymptomatic Smokers: Role of Nervous Mechanism in Small Airway Disease

Pulmonary function tests were performed on twenty eight males, among whom eight were healthy nonsmokers and twenty were asymptomatic smokers. Pulmonary function tests such as spirometry, respiratory impedance (Z3Hz), single breath nitrogen washout (SBN2) and volume of isoflow (VisoV) were done before and after inhalation of orciprenaline sulphate and atropine sulphate in all nonsmokers and smokers. Subdivisions of lung volume, diffusing capacity (DLco) and arterial blood gas analysis were conducted only before inhalation of drugs. Acute effects were studied after smoking a cigarette and effects of orciprenaline inhalation after smoking were also observed. Furthermore, effects of smoking on prior inhalation of orciprenaline, atropine or lidocaine were evaluated. The results obtained were as follows: 1) There were no differences in the results of routine pulmonary function tests, between nonsmokers and smokers except Z3Hz, which was significantly higher in smokers (p<0.01) and there was a tendency to decrease in flow especially at low lung volumes in smokers. Smokers could be well differentiated from nonsmokers by VisoV/FVC (p<0.001) and the difference in distribution of ventilation was greater (p<0.05). 2) In nonsmokers, Z3Hz decreased and V50 increased significantly after inhalation of orciprenaline and atropine. FEV1.o increased significantly with atropine inhalation only. There were no changes in VisoV/FVC with inhalation of orciprenaline or atropine. In smokers, Z3Hz and VisoV/FVC decreased significantly after inhalation of orciprenaline or atropine (p<0.001). FEV1.o and flow rates improved significantly with both drugs. 3) After smoking a cigarette, Z3Hz and VisoV/FVC significantly increased (p < 0.01), but inhalation of orciprenaline or atropine prior to smoking significantly inhibited the acute effects of smoking and lidocaine completely inhibited the acute effects of smoking. These results indicate that several parameters such as Z3Hz, flow at low lung volume, VisoV/FVC could detect the airway dysfunctions in asymptomatic cigarette smokers. These airway dysfunctions might be due to increased vagal tone, leading to narrowing of the airways and these airway dysfunctions were reversible by bronchodilator drugs.This study was performed in the Second Department of Internal Medicine, Hiroshima University School of Medicine, under a scholarship granted by The Ministry of Education, Science and Culture (Monbusho), The Government of Japan