Valved Holding Chamber Research Articles

Paediatric in vitro models showed significant variations in fluticasone proprionate output from valved holding chambers.

We compared potential differences in drug delivery between different valved holding chambers (VHCs) used by asthma patients, with and without facemasks. An in vitro study design was created using a fluticasone propionate (FP) pressurised metered dose inhaler (pMDI) connected to a VHC. VHCs without facemasks and with sealed and unsealed facemasks were placed against face models that mimicked the features of a 1-year-old infant and a 4-year-old child. We analysed the amount of FP deposited on the filter in the face model after five breaths with a tidal volume of 75mL. Our measurements showed significant differences in the amounts of FP deposited on the filters, even without facemasks. The amount of FP delivered through the VHC and facemask combinations differed significantly, depending on the degree of the lack of facemask to face seal. All the tested VHCs showed significantly better drug output without a facemask. The VHC and facemasks chosen had a considerable and significant impact on FP delivery. The facemask seal should be checked whenever a VHC facemask combination is used. Young children should be taught to use the VHC mouthpiece as early as possible to optimise FP delivery and achieve more effective asthma therapy.

In vitro evaluation of aerosol drug delivery with and without high flow nasal cannula in children.

To quantify aerosol delivery with or without a high flow nasal cannula (HFNC) in place using pressurized metered-dose inhaler (pMDI) and jet nebulizer (JN) with facemask in a simulated spontaneously breathing pediatric lung model. An upper airway model of a 9-month-old infant (Sophia Anatomical Infant Nose-Throat) with an absolute filter distal to the trachea was connected to a breathing simulator to simulate pediatric parameters (tidal volume = 100 mL, respiratory rate = 30 breaths/min, and I:E ratio = 1:1.4). Oxygen at 3 L/min was administered through an infant HFNC (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand) attached to the nares of the model. Albuterol sulfate (2.5 mg/3 mL) was delivered with JN attached to an aerosol facemask and powered by air at 8 L/min. Ventolin Hydrofluoroalkane (HFA) (360 μg) was administered using pMDI connected to a valved holding chamber (VHC) with a facemask. Aerosol was administered to the model with and without HFNC in the nares (n = 3). Drug was eluted from the filter and quantified using spectrophotometry. Independent t tests were performed for data analysis (P < .05). Aerosol deposition was greater without HFNC (6.05% ± 1.53% and 39.54% ± 8.98% for JN and pMDI/VHC, respectively) than with HFNC using JN (2.91% ± 0.23%; P = .024) and pMDI/VHC (6.04% ± 0.28%; P = .003). Delivery efficiency of pMDI/VHC was greater than JN with or without nasal cannula in place (P = .0001 and .003, respectively). Aerosol administered via facemask over HFNC was less efficient than removing HFNC during administration. When delivering medical aerosol by facemask, the benefit of increased aerosol delivery must be weighed against the changes in oxygen delivery and risk of lung derecruitment when nasal prongs are removed.

Comment on "Optimizing the Delivery of Inhaled Medication for Respiratory Patients: The Role of Valved Holding Chambers".

Comment on "Optimizing the Delivery of Inhaled Medication for Respiratory Patients: The Role of Valved Holding Chambers".

In vitro drug delivery performance of five valved holding chambers with and without facemasks

Valved holding chambers (VHCs) are essential for efficient pulmonary delivery of inhaled medication in preschool children. The numerous devices in the market vary in material, aerodynamic characteristics, volume, valve properties, and mask design. Drug delivery is affected by the VHC characteristics as well as by the age and breathing pattern of the child. We measured the drug delivery efficacy of five VHCs widely available in the market, evaluated the effect of facemasks and tested the differences between manufacturing lots. A breathing simulator was used to mimic normal (respiratory rate [RR] 25/minute and tidal volume (VT ) 200 mL) and obstructive (RR 50/minute and VT 50 mL) breathing of infants and toddlers. Salbutamol output was significantly higher with a normal breathing pattern compared to the obstructive breathing pattern in most VHCs. Without masks, the differences in the median in vitro filter doses of salbutamol were mainly from 2 to 10-fold among different types of VHCs. With masks, there was a greater than 20-fold difference in drug delivery capacity between the most and least effective devices. Most VHCs had a notable variation of performance between individual devices from different lots within the same brand. There was an extreme variation in the salbutamol delivery performance among different types of VHCs for both normal and obstructive pediatric breathing patterns with and without masks. This magnitude of performance variability can have significant and unpredictable clinical implications.

Comparing the Efficacy of Two Valved Holding Chambers in Acute Wheezing

Comparing the Efficacy of Two Valved Holding Chambers in Acute Wheezing

Valved holding chamber drug delivery is dependent on breathing pattern and device design.

Small children with airway obstruction breathe with very low tidal volumes (VT) and high respiratory rates (RRs). These extreme respiratory patterns affect drug delivery unpredictably through valved holding chambers (VHCs).We compared in an in vitro study the effectiveness of two VHCs, one small (140 mL, Optichamber Diamond) and one large (350 mL, Babyhaler) without facemasks, to deliver salbutamol to filters positioned between the VHC mouthpieces and a breathing simulator. Different tidal volumes (from 30 mL to 200 mL) and RRs (25·min-1 and 50·min-1) were applied through a breathing simulator.The amount of salbutamol delivered increased with increasing VT in both VHCs for both RRs (ρ>0.87 and p<0.001 for both devices at both rates). The effect of RR was not as evident, but drug delivery tended to be higher at the higher rate. Drug delivery was significantly higher through the Optichamber Diamond as compared with the Babyhaler at every combination of RR and VT up to a 12-fold difference.We found marked differences in salbutamol delivery between the Babyhaler and Optichamber Diamond VHCs. The delivered dose of salbutamol increased with increasing VT and RR with both VHCs but with differences related to valve dead spaces. Instead of considering all VHCs equal in clinical paediatric practice, each device should be tested in vitro with respiratory patterns relevant to small children with respiratory difficulties.

Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial.

In moderate-severe asthma exacerbation, salbutamol by inhaler (MDI) is superior to salbutamol delivered by nebulizer (NEB); however, to our knowledge, no studies in children with exclusively severe exacerbations were performed. To compare the efficacy of salbutamol and ipratropium bromide by MDI versus by NEB in severe asthma exacerbations. We performed a clinical trial enrolling 103 children (2-14 years of age) with severe asthma exacerbations (defined by the Pulmonary Score ≥ 7) seen at the emergency room in Asuncion, Paraguay. One group received salbutamol and ipratropium (two puff every 10 min for 2 h and then every 30 min for 2 h more) by MDI with a valved-holding chamber and mask along with oxygen by a cannula separately (MDI-SIB); and the other received nebulization with oxygen (NEB-SIB) of salbutamol and ipratropium (1 every 20 min for 2 h and then every 30 min for 2 h more). Primary outcome was the rate of hospitalization (Pulmonary Score ≥ 7) after 4 h and secondary outcome was oxygen saturation. Fifty two children received MDI-SIB and 51 NEB-SIB. After the 4th hour, children on MDI-SIB had significantly (P = 0.003) lower rate of hospital admission than on NEB-SIB (5.8% vs 27.5%, RR: 0.21 [0.06-0.69], respectively). Similarly, a significant improved clinical score after 60 min and increase in oxygen saturation after 90 min of treatment was observed in MDI-SIB versus NEB-SIB group (4.46 ± 0.7 vs 5.76 ± 0.65, P < 0.00001; and 90.5 ± 1.7 vs 88.43 1 ± 1, P < 0.00001, respectively). Even in severe asthma exacerbations administration of salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by a cannula separately was more effective than by a nebulizer.

A review of the in vitro and in vivo valved holding chamber (VHC) literature with a focus on the AeroChamber Plus Flow-Vu Anti-static VHC.

Valved holding chambers (VHCs) reduce the need for inhalation-actuation coordination with pressurized metered dose inhalers (pMDIs), reduce oropharyngeal drug deposition and may improve lung deposition and clinical outcomes compared to pMDIs used alone. While VHCs are thus widely advocated for use in vulnerable patient groups within clinical and regulatory guidelines, there is less consensus as to whether the performance differences between different VHCs have clinical implications. This review evaluates the VHC literature, in particular the data pertaining to large- versus small-volume chambers, aerosol performance with a VHC adjunct versus a pMDI alone, charge dissipative/conducting versus non-conducting VHCs, and facemasks, to ascertain whether potentially meaningful differences between VHCs exist. Inconsistencies in the literature are examined and explained, and relationships between in vitro and in vivo data are discussed. A particular focus of this review is the AeroChamber Plus® Flow-Vu® Anti-static VHC, the most recent iteration of the AeroChamber VHC family.

Optimizing the Delivery of Inhaled Medication for Respiratory Patients: The Role of Valved Holding Chambers.

Valved holding chambers (VHCs) have been used with pressurized metered-dose inhalers since the early 1980s. They have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce side effects such as throat irritation, dysphonia, and oral candidiasis that are common with use of pressurized metered-dose inhalers (pMDIs) alone. VHCs act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a two-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. The design of VHC devices can have an impact on performance. Features such as antistatic properties, effective face-to-facemask seal feedback whistles indicating correct inhalation speed, and inhalation indicators all help improve function and performance, and have been demonstrated to improve asthma control, reduce the rate of exacerbations, and improve quality of life. Not all VHCs are the same, and they are not interchangeable. Each pairing of a pMDI device plus VHC should be considered as a unique delivery system.

The Effect of a Holding Chamber on Albuterol Metered-Dose Inhaler Product Differences

JL Johnson, D Guthrie, J Hyde, T Hanson, K Karlage, PB Myrdal. Ann Allergy Asthma Immunol. 2016;117(3):246–250 To investigate the differences in 3 albuterol sulfate metered-dose inhaler (MDI) products and their particle size. The study also evaluated if use of a valved holding chamber (VHC) would impact drug delivery and/or diminish systemic adverse effects. The study did not use human subjects, but rather examined Ventolin hydrofluoroalkane (HFA), Proventil HFA, and ProAir HFA, the 3 racemic albuterol sulfate pressurized MDI products available in the United States. The experimental design involved a nonviable 8-stage Anderson Cascade Impactor (ACI) with a US Pharmacopeia (USP) throat model with a mean (SD) airflow rate of 28.3 (0.5) mL/min. Each of the 3 albuterol MDI products …

Are valved holding chambers (VHCs) interchangeable? An in vitro evaluation of VHC equivalence

IntroductionThe European Medicines Agency (EMA) requires that a specific valved holding chamber (VHC) is designated for use with a given pressurised metered dose inhaler (pMDI). No other regulatory authorities impose similar requirements, implying that VHCs are interchangeable. This in vitro study, employing EMA assessment criteria, assessed the equivalence of four anti-static VHCs (aVHCs) versus the non-conducting VHC most widely referenced in pMDI monographs, the AeroChamber Plus™ (AC+) VHC. Material & methodsThe “reference” AC + VHC was prepared by soaking in detergent solution. The four test aVHCs (AeroChamber Plus™ Flow-Vu™ [AC + FV]; Compact Space Chamber Plus [CSC+]; InspiraChamber [IC]; OptiChamber Diamond™ [OCD]) were tested “out-of-packet”. Twenty devices of each type were evaluated. A salbutamol pMDI was actuated into each VHC with a 2-s delay between actuation and Andersen Cascade Impactor (ACI) sampling. Drug deposition in four ACI particle size groups was assessed: Group 1, >5.8–10 μm; Group 2, >3.3–5.8 μm; Group 3, >1.1–3.3 μm; Group 4, ≤1.1 μm. Equivalence versus the reference VHC was demonstrated where the 90% confidence interval for the test/reference mass ratio was within 85–118%. ResultsThe mass retained within the VHC was similar for the AC + VHC and AC + FV aVHC, but was approximately twice as great for the other aVHCs. Salbutamol deposition in all ACI groups with the AC + FV aVHC was equivalent to the reference AC + VHC. By contrast, deposition in ACI groups 1 to 3 with the CSC+, IC and OCD aVHCs was inequivalent to (approximately half that of) the reference VHC. Inter-device variability for each VHC type was greatest for the IC and least for the AC + VHC and AC + FV aVHC. ConclusionsThe performance of VHCs that superficially resemble one another may differ markedly. Thus, as implied by EMA guidelines, VHCs should not automatically be considered to be interchangeable.

Use of a disposable valved-holding chamber (spacer) in a school-based asthma trial

Use of a disposable valved-holding chamber (spacer) in a school-based asthma trial

A Retrospective Study of the Effectiveness of the AeroChamber Plus® Flow-Vu® Antistatic Valved Holding Chamber for Asthma Control.

IntroductionElectrostatic charge in valved holding chambers (VHCs) may lead to inconsistent metered-dose inhaler (MDI) asthma drug delivery. We compared the AeroChamber Plus® Flow Vu® Antistatic Valved Holding Chamber (AC+FV AVHC) with non-antistatic control VHCs in terms of asthma exacerbations, resource use, and cost in an asthma population.MethodsPatients included in an adjudicated claims database with AC+FV AVHC or non-antistatic VHC (control VHC) use between 1/2010 and 8/2015 (index) who were treated with an inhaled corticosteroid (ICS) or a combination of an ICS and a long-acting β2 agonist MDI within 60 days before or after the index date, were diagnosed with asthma, and had ≥12 months of pre- and ≥30 days of post-index health plan enrollment were included. Cohorts were matched 1:1 using propensity scores. We compared incidence rates (IR) of exacerbation, time to first exacerbation using Kaplan–Meier survival analysis, occurrence of exacerbations, and healthcare resource use and costs using generalized linear models.Results9325 patients in each cohort were identified. The IR of exacerbations per 100 person-days (95% CI) was significantly higher in the control VHC cohort than the AC+FV AVHC cohort [0.161 (0.150–0.172) vs. 0.137 (0.128–0.147)]. A higher proportion of exacerbation-free patients was observed in the AC+FV AVHC cohort. Among the 4293 patients in each cohort with ≥12 months of follow-up, AC+FV AVHC patients were found to be 10–12% less likely than control VHC patients to experience an exacerbation throughout the study period. A lower proportion of the AC+FV AVHC patients had an ED visit compared to the control VHC patients (10.8% vs. 12.4%). Exacerbation-related costs for the AC+FV AVHC cohort were 23%, 25%, 20%, and 12% lower than those for the control VHC cohort at 1, 6, 9, and 12 months, respectively.ConclusionsThe AC+FV AVHC was associated with lower exacerbation rates, delayed time to first exacerbation, and lower exacerbation-related costs when compared to control non-antistatic VHCs.

Investigation of multiphase multicomponent aerosol flow dictating pMDI-spacer interactions

The use of Pressurized metered dose inhalers (pMDIs) for the treatment of asthma and other chronic obstructive pulmonary diseases is frequently associated with breath–actuation synchronization problems and poor pulmonary delivery, particularly amongst the pediatric and geriatric population groups. Spacers, or Valved Holding Chambers (VHCs), are frequently used to address these problems. However, the performance of spacers with different pMDIs is also highly variable and needs to be investigated. The purpose of the current study is to develop a computational fluid dynamics (CFD) model which can characterize multiphase multicomponent aerosol flow issuing from a commercial suspension-based pMDI into a spacer. The CFD model was initially calibrated against published experimental measurements in order to appropriately model the spray characteristics. This model was subsequently used to examine several combinations of inhaler, spacer and USP Throat geometries under different discharge rates of coflow air. The CFD model predictions compared favorably with experimental measurements. In particular, the predictions show, in accordance with experimental determinations, a decrease of drug retained by the spacers with increasing coflow air. The recirculation observed near the obstructions in axial path of the spray within either spacer is considered to be central for increasing spray retention and drug deposition behavior. Fluid flow patterns within the spacers were correlated with drug deposition behavior through a dimensionless variable, the Recirculation index (RCI). Bigger particles were found to be selectively retained within the spacer.

Asthma pressurised metered dose inhaler performance: propellant effect studies in delivery systems

BackgroundCurrent pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant‚ partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured.MethodsIn-vitro studies measured gas volumes produced by pMDIs on air oxygen (O2) levels in valved holding chambers (VHC) and the falls in O2% following actuation into lung ventilator delivery devices.ResultsVolumes of propellant gas hydrofluoroalkane (HFA) 134a and 227ea and redundant chlorofluorocarbons (CFC) varied from 7 ml per actuation from a small salbutamol HFA inhaler to 16 ml from the larger. Similar-sized CFC pMDI volumes were 15.6 and 20.4 ml. Each HFA salbutamol inhaler has 220 full volume discharges; total volume of gas from a small 134a pMDI was 1640 ml, and large 3885 ml. Sensing the presence of liquid propellant by shaking was felt at the 220th discharge in both large and small inhalers. Because of a partial pressure effect, VHC O2% in air was reduced to 11% in the smallest 127 ml volume VHC following 10 actuations of a large 134a salbutamol inhaler. The four ventilator delivery devices studied lowered 100% oxygen levels to a range of 93 to 81% after five actuations, depending on the device and type of pMDI used.ConclusionPressurised inhaler propellants require further study to assess smooth muscle relaxing properties.

A novel approach to study the pMDI plume using an infrared camera and to evaluate the aerodynamic properties after varying the time between actuations

Plume characteristics, such as temperature and velocity, emitted from pMDIs could significantly affect the dose delivered to the lung. Currently, high speed cameras and thermocouples are used separately to evaluate these parameters. We used a low-noise infrared camera to evaluate both the temperature and velocity of the emitted plume from pMDIs. Additionally, we investigated whether the fine particle fraction (FPF) is affected when time between actuations is varied. We tested three different albuterol sulfate pMDIs: ProAir® HFA, Proventil® HFA, and Ventolin® HFA. The plume and aerodynamic characteristics from these pMDIs were evaluated, after varying the time between actuations (15, 30, 60, and 120s), using the infrared camera and a next generation impactor, respectively. The aerodynamic characteristics were evaluated with and without a valved holding chamber (VHC). ProAir HFA had the softest plume followed by Proventil HFA and Ventolin HFA. Further, Ventolin HFA was slightly cooler and had significantly lower FPF than ProAir HFA and Proventil HFA. All inhalers had higher FPF when used with VHC. Further, we observed that the time between actuations affected the FPF across pMDIs. Moreover, generalized guidelines suggesting one-minute interval between actuations for pMDIs should be reconsidered, with and without a VHC.

The effect of a holding chamber on albuterol metered-dose inhaler product differences

BackgroundThree albuterol sulfate metered-dose inhaled (MDI) products (Ventolin HFA, Proventil HFA, and ProAir HFA) are marketed in the United States to provide the same total dose of albuterol sulfate. However, it is widely known that the fine particle dose (<5 μm) is the portion of the particle distribution that actually reaches the lungs and provides therapeutic benefit. ObjectiveTo examine the differences in particle size between products and how a valved holding chamber (VHC) can mitigate possible adverse effects. MethodsParticle size distributions in each product were measured, with and without a VHC, and were analyzed by high-performance liquid chromatography. ResultsThe only significant mean (SD) difference in total dose was between Proventil (75 [21] μg) and ProAir (107 [12] μg) (P < .01). The fine particle doses of all 3 products were significantly different: 21 (5) μg of albuterol sulfate for Ventolin, 40 (4) μg of albuterol sulfate for Proventil, and 64 (7) μg of albuterol sulfate for ProAir (P < .001 for all 3 cases). The VHC successfully removed the larger particle dose delivered by all 3 products (P ≤ .01) without reducing the fine particle dose (P > .05). ConclusionVentolin, Proventil, and ProAir should not be considered interchangeable products. In this study, the dose of albuterol sulfate likely to reach the lungs with Proventil or ProAir is 2 to 3 times that of Ventolin. As such, patients with asthma may require 3 additional puffs of Ventolin to achieve a clinical benefit similar to Proventil or ProAir. Because all 3 products contain 200 actuations, it also follows that Proventil or ProAir products may last a user 2 to 3 times longer than Ventolin.

Reducing Inpatient Length of Stay Using a Multicollaborative Protocol for Management of Non-Intensive Care Unit Asthmatics.

Maximizing clinical efficiency through the reduction in inpatient length of stay (LOS) using standardized protocols has been a major objective among hospital administrators, most notably in the context of recent healthcare reimbursement changes at statewide levels. The objective of our project was to determine whether a synchronous change in an inpatient asthma protocol that relied on a respiratory therapist (RT)-driven bronchodilator weaning algorithm and bronchodilator therapy given through a metered dose inhaler (MDI) plus valved holding chamber (VHC) could impact clinical and financial outcomes. A pre-post study assessed patients aged 2-21 years of age admitted with a primary diagnosis of status asthmaticus. The effect of the protocol was measured from October 2014 to July 2015. Outcome variables included patient demographics, hospital LOS, all-patient refined diagnosis-related groups (APR-DRGs), and inpatient charges. Outcomes were compared between the preimplementation and postimplementation time periods. Statistical significance was measured using Wilcoxon signed-rank test and bootstrap logistic regression models. Protocol patients (n = 110) had a similar demographic and clinical profile compared with the matched population from the previous nonprotocol fiscal year (n = 150). Use of the protocol resulted in a significantly reduced LOS that maintained significance after adjusting for APR-DRGs weight (P < 0.05). The protocol did not alter the total hospital billing charges. A nonstatistically significant reduction in 30-day readmission rates was observed among those administered the protocol. An RT-led weaning protocol using a quantitative scoring system and MDI+VHC for bronchodilator administration resulted in a significantly reduced LOS.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 26 Edinburgh International Conference Centre Edinburgh, Scotland, UK December 9-11, 2015.

The emitted dose of drug from a valved holding chamber using five pressurized metered dose inhalers

Background. The dose available at the mouth from a pressurised metered-dose inhaler (pMDI) cannot stay the same if it is used with a valved holding chamber (VHC). A different aerosol drug delivery system is created when the pMDI is used with the VHC and therefore the dose delivered to the patients is no longer that released from the pMDI alone, but the one emitted by the new system. This study aims to verify the emitted dose of five pMDI drugs when used with a VHC. Methods. The emitted dose was expressed as the amount of drug within the respirable fraction available at the end of the VHC, i.e. the drug output (measured by high performance liquid chromatography) multiplied by the percentage of FDF determined using a laser diffraction analyser. Results. the emitted doses were drastically reduced in comparison with the nominal doses (Beclomethasone from 250 to 90.5 µg, Budesonide from 200 to 100 µg, Ciclesonide from 160 to 102 µg Fluticasone from 250 to 116 µg, Salbutamol from 100 to 54 µg). Conclusions. When pMDIs are employed with a VHC, the emitted dose drastically changes; it is more or less halved. In order to facilitate prescription by the physician, both the nominal and the emitted doses should be reported in the VHC package.