NebuChamer - Questions and answers

- Why use a holding chamber?
  pMDIs produce aerosols that leave the device at high speed. This means that the patients have got very short time to inhale the dose. This can make the coordination of actuation and inhalation difficult, resulting in considerable oropharyngeal (mouth and throat) drug deposition and variability in lung dose. The use of holding chambers slows the aerosol cloud, thereby eliminating the need for coordination of actuation and inhalation. As a result, oropharyngeal deposition is reduced, and hence the therapeutic ratio is improved. The combination of pMDI and holding chamber provides a particularly useful means of drug delivery in children, who are often unable to use a pMDI correctly (Bisgaard, 1995; Bisgaard et al, 2002; Janssens, 2001).
  
  References
  Bisgaard H. Delivery of inhaled medication to children. J Asthma 1995;34:443-67.
  Bisgaard H, et al. Spacer devices. In: Drug delivery to the lung. Bisgaard H, O’Callaghan C, Smaldone GC, eds. Marcel Dekker, New York; 2002;389-420.
  Janssens HM. Aerosol delivery in young children. Thesis. Erasmus University, Rotterdam, The Netherlands. 2001.
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- Is NebuChamber® free of electrostatic charges?
  NebuChamber^® is made from stainless steel and is not susceptible to electrostatic charge, unlike many plastic spacers and valved holding chambers. Electrostatic charges act as interfering forces on the drug particles released into plastic spacers or valved holding chambers when the pMDI is actuated. The electrostatic effects are most pronounced for the first doses released in the chamber.
  In contrast to traditional plastic holding chambers, NebuChamber does not need to be “primed”, i.e. NebuChamber delivers a full dose already from the first actuation of the pMDI.
  The effects of priming were investigated in vivo in a study by Kenyon et al comparing NebuChamber with Nebuhaler^® and Volumatic™. Priming NebuChamber with 20 doses of placebo aerosol did not result in any substantial increase in total lung deposition compared with an unprimed NebuChamber.
  Active doses consisted of budesonide 200 µg labelled with 99mTc. “Priming” consisted of firing 20 doses into the valved holding chamber. Lung deposition was measured by gamma scintigraphy. Adapted from Kenyon et al (1998).
  Volumatic™ is a trademark owned by the GlaxoSmithKline group of companies.
  
  References
  Further reading:
  Kenyon CJ, et al. The effects of static charge in valved holding chambers on glucocorticosteroid aerosol deposition in asthmatic patients. Eur Respir J 1998;11:606-10.
  Bisgaard H, et al. A non-electrostatic valved holding chamber for aerosol delivery. Arch Dis Child 1995;73:226-30.
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- Does NebuChamber® deliver a consistent dosing?
  The lack of electrostatic interference on the walls of NebuChamber^® means that the dose delivered from NebuChamber will be consistent over time.
  Repeated use of a pMDI in combination with NebuChamber gave a consistent delivery of dose over 100 consecutive doses of budesonide in vitro (Berg et al, 1998).
  The drug used in this study was budesonide. Adapted from Berg et al (1998).
  Pulmicort^® NebuChamber^® also delivers inhaled budesonide in young children independent of age. In a study in 124 children, age 6 months to 6 years, the mean dose of budesonide delivered to the children was 39% of the nominal dose, which was similar across different age groups 0-2 years, 2-4 years and 4-6 years (Bisgaard et al, 1995).
  Dose delivery from NebuChamber in asthmatic children of different ages. Doses were measured by interposing a filter between the facemask and the valve system of the holding chamber. Adapted from Bisgaard et al (1995).
  In a study by Barry and O'Callaghan (1999), in which a breathing simulator mimicked the effect of breathing at tidal volumes between 50 and 300 mL with a respiratory frequency of 20 cycles/min, the delivery of budesonide from NebuChamber was constant at tidal volumes of 150 mL and above (Figure). Thus, for the youngest children with small tidal volumes (50 ml corresponds approximately to 5 kg body weight) less drug will be delivered – however, calculated per kg body weight twice as much budesonide will be delivered compared to older children.
  Amounts of budesonide deposited on filters from NebuChamber and Nebuhaler at different tidal volumes after 5 inhalations. Holding chambers were washed in warm water and air-dried. Adapted from Barry and O’Callaghan (1999).
  References
  Berg E, et al. In vitro performance of three combinations of valved holding chambers and pressurized metered dose inhalers for treatment in children. Eur Respir J 1998;12:472-6.
  Bisgaard H, et al. A non-electrostatic valved holding chamber for aerosol delivery. Arch Dis Child 1995;73:226-30.
  Barry PW, O'Callaghan C. The output of budesonide from spacer devices assessed under simulated breathing conditions. J Allergy Clin Immunol 1999;104:1205-10.
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- Does NebuChamber® deliver a high proportion of drugs as fine droplets?
  Correct use of a pMDI in combination with NebuChamber^® results in a high proportion of the metered dose delivered as fine droplets (< 4.7 µm) (Berg et al, 1998). Fine particle dose is considered to be proportional to the dose available to the lungs.
  This study compared the dose output of fine droplets from NebuChamber. The output of fine particles was calculated based on the dose delivered by the valved holding chambers when connected to a ventilator set to simulate the breathing pattern of a young child. NebuChamber delivered a high portion of fine droplets.
  The drug used in this study was budesonide. Adapted from Berg et al (1998).
  Reference
  Berg E, et al. In vitro performance of three combinations of valved holding chambers and pressurized metered dose inhalers for treatment in children. Eur Respir J 1998;12:472-6.
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- Is NebuChamber® sensitive to delays in emptying?
  As drug particles tend to settle on the walls of the holding chamber it is important not to wait before inhaling. However, this may not always be possible when administering inhaled drugs to young children.
  
  NebuChamber^® is relatively unaffected by delays in emptying in contrast to Nebuhaler^®. In one study (Berg et al,2001), drug output from the holding chamber was collected with delays of 0, 5 and 15 s between actuation of the pMDI and the start of collection. With Pulmicort^® pMDI plus NebuChamber the median output only decreased from 49% when collection was started at the same time as actuation to 32% with a 15s delay.
  
  Reference
  Berg E, et al. Impact of inspiratory delay and valved holding chamber (VHC) material on drug delivery. Am J Respir Crit Care Med 2001;163(suppl 2):A441.
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- Is the performance dependent of washing or drying procedures?
  Washing procedures affect the charge on traditional plastic holding chambers; therefore, washing may cause variation in the dose delivered. Washing procedures have no effect on the delivery of drug from NebuChamber^® because it is entirely free from electrostatic charge.
  Regardless of whether NebuChamber was new, primed with 15 doses of drug aerosol, or washed and rinsed, NebuChamber consistently provided an environment where over half of the drug-containing droplets remained airborne (aerosol half-life) for nearly 30 seconds (Berg et al, 1998).
  The drug used in this study was budesonide. Adapted from Berg et al (1998).
  Reference
  Berg E, et al. In vitro performance of three combinations of valved holding chambers and pressurized metered dose inhalers for treatment in children. Eur Respir J 1998;12:472-6.
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- Which are the dose delivery studies with Nebuchamber® performed in asthmatic patients?
  The ex vivo output of budesonide (Pulmicort^®) from NebuChamber^® and other holding chambers (including Nebuhaler^®) has been investigated in children aged 6 months to 6 years with suspected asthma (Bisgaard et aI, 1995). The children inhaled budesonide via CFC pMDI with NebuChamber and Nebuhaler, and the mean dose delivered with NebuChamber was 39% of the nominal dose and 21% with Nebuhaler. Thus, the ex vivo drug delivery corresponded to the figures found in vitro. This is consistent with the findings of Berg et al(1998) that drug delivery during simulated breathing was comparable with the maximum output measured in vitro.
  
  In a study in adult patients with mild asthma, lung deposition of budesonide (Pulmicort pMDI) with NebuChamber and Nebuhaler was investigated. Priming the holding chambers had no effect on lung deposition from NebuChamber (unprimed 32.9%, primed 33.5%) but it significantly increased lung deposition from Nebuhaler (unprimed 26.7%, primed 37.7%; p=0.01) (Kenyon et aI,1998). For both devices, deposition in the central, intermediate and peripheral zones of the lung increased equally, and therefore there was no change in the distribution of budesonide deposition in the lungs.
  
  Drug deposition with NebuChamber was equivalent to that seen with Nebuhaler, despite the fact that the volume of NebuChamber is only about one third that of the other device.
  
  References
  Berg E, et al. In vitro performance of three combinations of valved holding chambers and pressurized metered dose inhalers for treatment in children. Eur Respir J 1998;12:472-6.
  Bisgaard H, et al. A non-electrostatic valved holding chamber for aerosol delivery. Arch Dis Child 1995;73:226-30.
  Kenyon CJ, et al. The effects of static charge in valved holding chambers on glucocorticosteroid aerosol deposition in asthmatic patients. Eur Respir J 1998;11:606-10.
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- Are there any lung deposition studies with Nebuchamber® in children?
  NebuChamber^® has been used to investigate lung deposition and systemic availability of Pulmicort^® pMDI in children and adults (Anhøj et al, 2000). The study showed that there were no significant differences between children and adults in the dose delivered to the patient, the systemic exposure to budesonide (as measured by AUC), or the elimination half-life (Table). Since both the dose to patient and systemic exposure were similar in young children and adults, the systemic dose must have been increased in adults compared with children. This is probably due to the smaller lungs in children, which results in a lower lung deposition compared with adults. This suggests that it is not necessary to adjust the dose of budesonide to minimise the risk of systemic adverse effects in children when budesonide is delivered via pMDI plus NebuChamber.
  Pharmacokinetic parameters after inhalation of Pulmicort 400 µg via CFC pMDI with NebuChamber in children aged 2–3 or 4–6 years and adults (Anhøj et al, 2000). Results are presented as means and 95% confidence intervals.
  *Geometric mean, C20: plasma concentration at 20 min.
  Adapted from Anhøj et al (2000).
  Reference
  Anhøj J, et al. Lung deposition of inhaled drugs increases with age. Am J Respir Crit Care Med 2000;162:1819-22.
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- Mouthpiece or face mask with holding chambers?
  Face masks, rather than mouthpieces, are necessary when using holding chambers with children aged less than 2–3 years. This, however, allows nose breathing, which reduces the lung dose. Mouthpieces provide more efficient drug delivery to the lungs, and should therefore be used in preference to face masks as early as possible (O'Callaghan and Barry, 2000).
  The delivery of budesonide (Pulmicort^®) via NebuChamber^® with face mask in children aged 1–4 years and via NebuChamber with mouthpiece in children aged 5–8 years (Janssens et al,1999) has been reported. In the younger children, the mean filter dose was 41.7% with NebuChamber and the variability in dosing was 34%; in the older children, the mean filter dose was 50.2% with NebuChamber and the variability was 23%. This shows that the delivered dose is not greatly reduced when using a face mask with NebuChamber, but variability in delivered dose slightly increased.
  Overall, the highest delivered doses and lowest dose variabilities are seen with smooth, round masks that provide a good fit over the mouth. However, the face mask should be replaced with a mouthpiece as soon as a child is able to use it (O'Callaghan and Barry, 2000).
  
  References
  O'Callaghan C, Barry PW. How to choose delivery devices for asthma. Arch Dis Child 2000;82:185-7.
  Janssens HM, et al. Variability of aerosol delivery via spacer devices in young asthmatic children in daily life. Eur Respir J1999;13:787-91.
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- Which face mask should be used with Nebuchamber®?
  The face mask supplied with NebuChamber^® is contoured to the face of a young child. Although preferred during ideal conditions, the preformed shape may not fit all faces of infants. Thus, in order to minimize leaks it is important that the face mask fit is checked, and if a good fit is not achieved, another face mask can be used. A smooth, round mask that provides a good fit to the mouth may be an alternative.
  
  Reference
  Amirav I. Infant aerosol holding chamber face masks: not all are born equal! Respir Care 2006;51(2):123-5.
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- Can Nebuchamber®be used in very small children?
  Inhaled therapy in very small children (e.g. infants with chronic lung disease of prematurity (CLD)) present particular challenges because breathing patterns are often irregular and tidal volumes and inspiratory flows are low and highly variable (Bisgaard et al, 2002). As a result, the factors that influence drug delivery from holding chambers—such as chamber volume, electrostatic charge, and drug loss through the valve assembly—have a marked impact on drug delivery in neonates. Such holding chambers should therefore have a small volume and a low-resistance inspiratory and expiratory valve system, and should be made of non-electrostatic material.
  An ex vivo study (Turpeinen et al, 1999) in 13 infants aged 2–19 months (of these 6 children had been born preterm) showed a high and constant dose delivery from NebuChamber^® in the range of 50–200 mL tidal volumes. A further in vitro study (Janssens et al, 2001) showed that the proportion of an inhaled dose of budesonide delivered from NebuChamber as particles less than 4.7 µm was approximately 12% in infants with a tidal volume of 50 mL (Figure).
  NebuChamber also offers the advantage in neonates that only low flow rates are needed to open the inspiratory valves. In an in vitro study (Berg et al, 2002) it was found that the valve could open at flow rates as low as 0.5 litres/minute. Such flow rates can be achieved early in the inspiratory cycle in young children, and even in neonates (Stocks, 1999).
  Deposition of budesonide from NebuChamber^® in a model that allows investigation of factors affecting inhaled drug delivery to neonates (Janssens et al, 2001). Note that the decrease in drug delivery seen at higher tidal volumes reflects a higher deposition of drug particles in the nose because of higher inspiratory airflows by older children.
  References
  Berg E, et al. NebuChamber^® —valve opening at very low inspiratory flow rates. Eur Respir J 2002;20(Suppl 38):172s, Abs 1114.
  Bisgaard H, et al. Spacer devices. In: Bisgaard H, O'Callaghan C, Smaldone GC, editor(s). Drug delivery to the lung. New York: Marcel Dekker, 2002:389-420.
  Janssens HM, et al. The Sophia Anatomical Infant Nose-Throat (SAINT) model: A valuable tool to study aerosol deposition in infants. J Aerosol Med 2001;14(4):433-41.
  Stocks J. Lung function testing in infants. Pediatr Pulmonol Suppl 1999;18:14-20.
  Turpeinen M, et al. Metered dose inhaler add-on devices: Is the inhaled mass of drug dependent on the size of the infant? J Aerosol Med 1999;12(3):171-6.
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- Nebuchamber® summary
  Young children and infants are often incapable or unwilling to participate in drug delivery. A pMDI in combination with a non-electrostatic valved holding chamber and a face mask has been highlighted as the preferred inhaled drug delivery system for infants and young children. The design of NebuChamber^® makes it particularly suitable for children:
  - Short periods of apnoea are common among young children, especially when a facemask is used. NebuChamber provides a delivery system, which accommodates the variable breathing patterns of children.
  - The 250 mL volume, with a dead space of only 1 mL, allows for a more concentrated drug aerosol than with larger holding chambers. This enables easy inhalation by infants and young children with small tidal capacities.
  The review by Bisgaard of systems for delivery of inhaled medication recommends the use of a pMDI with a valved holding chamber device and a face mask for infants and young children. It also highlights the need for non-electrostatic valved holding chambers to ensure consistent drug delivery.
  Reference
  Bisgaard H. Delivery of inhaled medication to children.J Asthma 1997;34(6):443-67.
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- Alternative names for NebuChamber®
  Alternative names for NebuChamber^®
  
  Alternative trademarks for NebuChamber^® include: Nebunette^® and NES-Spacer^®.
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