Use of Metered Dose Inhalers, Spacers, and Nebulizers

Metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers are modes of aerosol drug delivery that are used to treat respiratory disorders (eg, asthma, obstructive lung disorders, cystic fibrosis, pulmonary arterial hypertension, infectious pulmonary disease). ^[1] A spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

A diagram of an MDI is shown in the image below.

Metered dose inhalers (MDIs)

An MDI is a handheld aerosol device that uses a propellant to deliver the therapeutic agent.

Advantages of MDIs are as follows:

• Portability
• Multidose delivery capability
• Lower risk of bacterial contamination ^[2]

Disadvantages of MDIs are as follows:

• Need for correct actuation and inhalation coordination ^{[3, 4]}
• Oropharyngeal drug deposition ^[2]

Dry powder inhalers (DPIs)

A DPI is a breath-actuated device that delivers the drug in the form of particles contained in a capsule or blister that is punctured before use.

Advantages of DPIs include the following:

• Breath-actuated
• Spacer not necessary
• No need to hold breath after inhalation
• Portable
• No propellant

Disadvantages of DPIs include the following:

• Adequate inspiratory flow required for medication delivery
• May result in high pharyngeal deposition
• Humidity potentially causes powder clumping and reduced dispersal of fine particle mass

Inhalation accessory devices (IADs)

Inhalation accessory devices (IADs) generally fall into 2 categories: spacers and holding chambers. A spacer is an extension add-on device that permits the aerosol plume from the MDI to expand and slow down, turning it into a very fine mist instead of a high-pressure actuation spray. Valved holding chambers allow for a fine cloud of medication to stay in the spacer until the patient breathes it in through a one-way valve, drawing the dose of medication into the lungs.

Advantages of IADs are as follows:

• Enhanced drug delivery
• Compensation for poor technique/coordination with MDI
• Reduced oropharyngeal deposition

Disadvantages of IADs are as follows:

• Large size and volume of device
• Bacterial contamination is possible; device needs to be cleaned periodically
• Electrostatic charges may reduce drug delivery to the lungs

Nebulizers

Nebulizers are devices that transform solutions or suspensions of medications into aerosols that are optimal for deposition in the lower airway.

The following are advantages of nebulizers:

• Provide therapy for patients who cannot use other inhalation modalities (eg, MDI, DPI)
• Allow administration of large doses of medicine
• Patient coordination not required

The following are disadvantages of nebulizers:

• Decreased portability
• Longer set-up and administration time
• Higher cost
• May need source of compressed air or oxygen (jet nebulizer)

Introduction

Drug delivery mechanisms using aerosols are an integral part of the treatment of respiratory disorders (eg, asthma, obstructive lung disorders, cystic fibrosis, pulmonary arterial hypertension, ^[5] infectious pulmonary disease). With the advent of novel macromolecular medications, the horizon of aerosol drug delivery is expanding to include nonrespiratory conditions (eg, diabetes, analgesia, thyroid disorders, genetic disease).

Metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers are the popular modes of aerosol delivery. A spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination. ^[6] The inherent advantages of aerosol drug delivery are a faster onset of pharmacologic action, because the drug is being delivered to the site that requires a therapeutic effect, and a lower systemic bioavailability, which decreases potential adverse effects. ^[7]  

Indications

This mode of delivery is indicated when the drug can be converted into an aerosol form for inhalation. ^[8]

Contraindications

Contraindications to the use of these devices are as follows:

• Sensitivity or cardiotoxicity to propellants is a contraindication for MDI use.

• DPIs are not indicated in patients who cannot generate an adequate inspiratory flow rate. ^[9]

• No contraindications exist to the use of spacers and nebulizers. ^{[6, 10, 11]}

Equipment

A metered dose inhaler (MDI) is a handheld aerosol device that uses a propellant to deliver the therapeutic agent. MDIs include a pressurized metal canister that contains the following ^{[2, 12]} :

• Pharmacologic agent in suspension or solution

• Surfactant

• Propellant

• Metering valve

The canister is housed in a plastic sleeve that has a mouthpiece for drug delivery.

Actuation (ie, triggering of the canister) produces a fine atomized spray over 100-200 milliseconds that delivers the dose (the delivered dose varies with the particular medication). Most particles have high inertia, and most of the output at the orifice of the actuation consists of droplets that are large (25 microns) and have high velocities (30 m/s). ^{[2, 8, 12, 13]} This results in oropharyngeal deposition; only a minute fraction of the dose deposits in the lungs. ^{[2, 8, 12]}

The pharmacologic agent in a suspension formulation results in a 10% respirable fraction; an agent in a dilute solution formulation with a volatile propellant blend may result in up to a 40% respirable fraction. The surfactant stabilizes the suspension by preventing caking.

Various MDIs and an MDI diagram are shown in the images below.

Advantages of MDIs are as follows:

• Portability

• Multidose delivery capability

• Lower risk of bacterial contamination ^[2]

Disadvantages of MDIs are as follows:

• Need for correct actuation and inhalation coordination ^{[3, 4]}

• Oropharyngeal drug deposition ^[2]

• Possible flammability of hydrofluoroalkane (HFA) propellants ^[14]

Specific information regarding different MDIs and the amount of drug per actuation for each are provided in Table 1 below.

Table 1. Metered Dose Inhalers (MDIs) and the Amount of Drug per Actuation (Open Table in a new window)

 

Subsequent to the Montreal Protocol on Substances that Deplete the Ozone Layer, chlorofluorocarbon (CFC) propellants (implicated in ozone depletion) have been phased out in favor of the organic compound hydrofluoroalkane (HFA), which is not known to cause ozone depletion. ^{[15, 16]} MDIs that use CFC have been replaced by those that use HFA-134a. ^{[17, 18]}

These new devices are not only more environmentally friendly but, surprisingly, are also more effective. The HFA propellant produces an aerosol with smaller particle size, resulting in improved deposition in the small airways and greater efficacy at equivalent doses compared with CFC MDIs.

The United States Food and Drug Administration (FDA) published an update in 2010 regarding the progress that the US was making with its obligations under the Montreal agreement. ^[17] Seven MDIs that contain CFCs were still on the US market at that time, but they have been phased out. Alternatives to some of these medications (eg, dry powder formulations) are available. For additional information, see the FDA website.

Dry powder inhalers

A dry powder inhaler (DPI) is a breath-actuated device that delivers the drug in the form of particles contained in a capsule or blister that is punctured prior to use. ^[19]  This type of inhaler requires an adequate inspiratory flow rate for drug delivery, as it does not include a propellant. ^[20] Because of this inspiratory flow rate requirement, DPIs are not appropriate for treatment of acute asthma attacks.

The degree of resistance to inspiratory flow required to aerosolize the medication varies with each of the multiple versions of DPIs. ^[9]  Low-resistance devices are suitable for the treatment of children and those with decreased lung function (forced expiratory volume in 1 second [FEV₁] < 30% of predicted), ^[21] whereas high-resistance devices require a higher inspiratory flow rate to aerosolize an equivalent drug dose. For a comparison of DPI drug delivery amounts, see Table 2 below.

Table 2. Dry Powder Inhalers (DPIs) (Open Table in a new window)

 

DPI devices include the following (also see the images below):

• Diskus

• Aerolizer

• HandiHaler

• Twisthaler

• Flexhaler

The Diskus (eg, Advair, Flovent), shown below, is a blister pack, unit-dose device. The pack consists of a coiled, double-foil strip of 60 blisters, each containing one dose of drug powder with a lactose carrier. ^[9] The drug dose for this device ranges widely (50-500 mcg), depending on the product. During inhalation, each blister is moved into place and its lid-foil is peeled away by a contracting wheel. The inhaled air is drawn through the opened blister, aerosolizing and delivering the dose through the mouthpiece. ^[21]

An Aerolizer inhaler, shown below, is a device used for formoterol fumarate (Foradil) inhalation, a long-acting selective beta2-adrenergic agonist. ^[22] To use, a formoterol capsule is placed in the Aerolizer inhaler well, and the capsule is pierced by pressing and releasing the button on the side of the device. This permits the formoterol fumarate formulation to disperse into the air stream when the patient inhales rapidly and deeply through the mouthpiece. ^[23]

HandiHaler, depicted in the image below, is an inhalation device used to deliver the dry powder tiotropium bromide (Spiriva), a long-acting anticholinergic agent. ^[24] The tiotropium capsule is placed in the center chamber of the HandiHaler, and the capsule is pierced by pressing and releasing the green button. This leads to the dispersal of tiotropium formulation into the air stream when the patient inhales through the mouthpiece.

A Twisthaler, shown below, is an inhalation device that delivers the fine dry powder mometasone furoate (Asmanex), an inhaled corticosteroid. ^[9]

The Flexhaler, depicted below, is an inhalation device used to deliver the dry powder budesonide (Pulmicort), an anti-inflammatory synthetic corticosteroid. The Flexhaler has replaced the Turbuhaler, which is no longer marketed. The budesonide capsule is placed in the center of the chamber of the Flexhaler, and the capsule is pierced by twisting the device fully one way and then back fully the other way. This allows the budesonide formulation to disperse into the air stream when the patient inhales rapidly and deeply through the mouthpiece.

DPI advantages include the following:

• Breath-actuated

• Spacer not necessary

• No need to hold breath after inhalation

• Portable

• No propellant

DPI disadvantages include the following:

• Adequate inspiratory flow required for medication delivery

• May result in high pharyngeal deposition

• Humidity potentially causes powder clumping and reduced dispersal of fine particle mass

Inhalation accessory devices

Inhalation accessory devices (IADs) generally fall into 2 categories: spacers and holding chambers. Using a spacer device with an MDI can help reduce the amount of drug that sticks to the back of the throat, improving direction and deposition of medication delivered by MDIs. Spacers and holding chambers extend the mouthpiece of the inhaler and direct the mist of medication toward the mouth, reducing medication lost into the air.

Spacers

A spacer, shown below, is an extension add-on device that permits the aerosol plume from the MDI to expand and slow down, turning it into a very fine mist instead of a high-pressure actuation spray. The cloud of vapor is so fine that most patients do not feel or taste it as they breathe it in. The fine drug particles are carried deep into the lung, where they are most effective, instead of hitting the tongue or the back of the throat the way a blast from an MDI sometimes does. ^{[6, 25]}

Spacers attempt to address the problem of patient coordination between device actuation and breath. When using a spacer, however, the patient must still coordinate the breath to occur slightly before actuation. ^{[10, 26]}

For information on features of particular spacers, see Table 3 and Table 4 below.

Table 3. Open Tube Spacers (Open Table in a new window)

 

Table 4. Reverse-Flow Spacers (Open Table in a new window)

 

Valved holding chambers

Valved holding chambers (VHCs) allow for a fine cloud of medication to stay in the spacer until the patient breathes it in through a one-way valve, drawing the dose of medicine into the lungs. Examples include Aerochamber and Optichamber. For more information on VHC features, see Table 5 below.

Use of a spacer or VHC is recommended with inhaled corticosteroids to minimize such effects as thrush and hoarseness. ^[7] Children aged 4 years or younger should use a VHC with a mask. ^[7]

Table 5. Valved Holding Chambers (VHCs) (Open Table in a new window)

 

Advantages of IADs are as follows:

• Enhanced drug delivery

• Compensation for poor technique/coordination with MDI

• Reduced oropharyngeal deposition

Disadvantages of IADs are as follows:

• Large size and volume of device

• Bacterial contamination is possible; device needs to be cleaned periodically

• Electrostatic charges may reduce drug delivery to the lungs

Nebulizers

Nebulizers are devices that transform solutions or suspensions of medications into aerosols that are optimal for deposition in the lower airway. This mode of aerosol drug delivery is critical for respiratory disorders and may include corticosteroids, bronchodilators, anticholinergics, antibiotics, and mucolytic agents. Inhalation solution doses are shown in Table 6.

Table 6. Inhalation Solutions Often Used with Nebulizers (Open Table in a new window)

 

Nebulization provides a vehicle for drug delivery to patients who are too ill or too young to use other portable inhaler devices. ^[11] The 2 types of nebulizers are pneumatic jet nebulizers and ultrasonic nebulizers.

A pneumatic jet nebulizer (see images below) delivers compressed gas through a jet, causing an area of negative pressure and drawing the liquid up the tube by the Bernoulli effect. The solution is entrained into the gas stream and then sheared into a liquid film that is unstable and is broken into droplets by surface tension forces. The fundamental concept of nebulizer performance is the conversion of the medication solution into droplets in the respirable range of 1-5 micrometers. ^[27]

An ultrasonic nebulizer generates high-frequency ultrasonic waves (1.63 MHz) from electrical energy via a piezoelectric element in the transducer. These ultrasonic waves are transmitted to the surface of the solution to create an aerosol. Aerosol delivery is by a fan or the patient’s inspiratory flow; particle sizes may be larger with this device. A limitation of ultrasonic nebulizers is that they do not nebulize suspensions efficiently. ^[11]

Ultrasonic nebulizers may be used with all nebulized medications except Pulmicort Respules suspension (most nebulized medications are solutions). Pulmicort Respules cannot be used with nebulizer units that generate heat, as is the case with most ultrasonic nebulizers (with the exception of the Omron MicroAir).

The following are advantages of nebulizers:

• Provide therapy for patients who cannot use other inhalation modalities (eg, MDI, DPI)

• Allow administration of large doses of medicine

• Patient coordination not required

• No CFC release

The following are disadvantages of nebulizers:

• Decreased portability

• Longer set-up and administration time

• Higher cost

• May need source of compressed air or oxygen (jet nebulizer)

Positioning

MDIs, DPIs, and nebulizers are used with the patient sitting up comfortably straight.

The technique for metered dose inhaler (MDI) use is as follows:

• Take off the cap and hold the inhaler upright.

• Shake the inhaler.

• Tilt the head back slightly and slowly breathe out completely for 3-5 seconds.

• Use the device in 1 of the 3 positions shown in the image below; positions A and B are best, but position C can be used if the patient has trouble with A or B.

  Metered dose inhaler (MDI) positioning.

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• Simultaneously breathe in slowly through the mouth and press down on the inhaler 1 time to release the medication; if using a holding chamber, first press down on the inhaler and then begin to breathe in slowly within 5 seconds.

• Keep breathing in slowly, as deeply and evenly as possible.

• If possible, hold the breath while counting to 10 slowly; this allows the medicine to reach deep into the lungs.

• Repeat the above process if more than 1 puff (actuation) is prescribed.

• Wait 1 minute between actuations; this may improve penetration of the second actuation into lung airways.

Dry powder inhalers (DPIs) are breath activated; when the patient breathes, the inhaler releases the medicine into the patient's lungs. DPIs include the Diskus, Aerolizer, HandiHaler, Twisthaler, and Flexhaler. General instructions for use are as follows:

• After opening the inhaler and loading the dose, tilt the head slightly back.

• Exhale before positioning the inhaler.

• Position the inhaler horizontally, with the outlet between the lips, slightly inside the mouth.

The technique for use differs with the particular device. The technique for the Diskus is as follows:

• Open the device and trigger the lever until a click is heard; at the click, the dose is ready for delivery through inhalation.

• Seal lips around the Diskus orifice (ie, mouthpiece), as shown in the image below.

  Diskus positioning.

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• Hold the Diskus horizontally during inhalation.

• Breathe in deeply and steadily; hold breath for a few seconds.

• Disengage the device from the mouth and exhale.

The technique for use of the Aerolizer is as follows:

• Remove the cover and hold the base of the inhaler, as shown in the image below.

  Aerolizer outer structure schematic.

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• Twist the mouthpiece in a counterclockwise direction.

• Place the capsule from the blister into the well at the base of the inhaler.

• Turn the base clockwise to close.

• Press both buttons to pierce the capsule.

• Hold the device in a horizontal orientation and breathe in deeply.

• Hold breath for up to 10 seconds.

• Disengage the device from mouth and exhale.

• Open the chamber and examine the capsule, as shown in the image below; if powder remains, repeat the steps above.

  Aerolizer inner structure schematic.

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• Remove and discard capsule and cover mouthpiece.

The technique for the HandiHaler is as follows:

• Remove capsules from the blister package only prior to use.

• Place the capsule in the center chamber.

• Close the mouthpiece firmly until a click is heard, leaving the dust cap open.

• Hold the inhaler upright; press the piercing button completely in once and release.

• Hold the device in a horizontal orientation and breathe in deeply.

• Hold breath for up to 10 seconds.

• Disengage the device from mouth and exhale.

• After the dose, open the mouthpiece, remove the used capsule, and dispose of it.

• Cover the mouthpiece and dust cap for storage.

The technique for the Twisthaler is as follows:

• Hold the inhaler straight up with the pink portion (the base) at the bottom.

• Hold the pink base and twist the cap in a counterclockwise direction to remove it.

• As the cap is lifted, the dose counter on the base counts down by 1; this action loads the medicine, which is now ready for inhalation.

• Make sure the indented arrow located on the white portion (directly above the pink base) is pointing to the dose counter.

• Hold the Twisthaler device in a horizontal orientation and breathe in deeply.

• Hold breath for up to 10 seconds.

• Disengage the device from mouth and exhale.

• Replace the cap and turn in a clockwise direction; gently press down until a click is heard.

• Close the Twisthaler to ensure that the next dose is properly loaded.

• Confirm that the arrow is in line with the dose counter window; this shows how many doses are left in the Twisthaler.

• If another dose is needed, repeat the steps above.

• When the dose counter window reads "01," this signifies the last dose of medicine in the Twisthaler.

• When the cap is replaced after the last dose, the cap locks and the Twisthaler must be thrown away.

• Rinse the mouth out with water and spit (do not swallow the water).

The technique for the Flexhaler is as follows:

• Prime the inhaler before first use by twisting the brown grip as far as it will go in one direction (until a click is heard).

• Load dose by twisting cover and lifting it off.

• Hold the inhaler in an upright position with the mouthpiece up when loading the dose.

• Twist the brown grip fully in one direction as far as it will go; twist it fully back again in the other direction (until a click is heard).

• Breathe out fully while turning the head away from the inhaler; do not shake the device.

• Insert the mouthpiece into the mouth and close the lips around it without biting or chewing on the mouthpiece.

• Inhale deeply and forcefully through the inhaler.

• If more than 1 dose is required, repeat the steps above.

• When finished, place the cover back on the inhaler and twist shut.

• Rinse the mouth out with water.

The technique for an inhalation accessory device (IAD) is as follows:

• Attach the MDI to a spacer or valved holding chamber.

• Shake the canister and hold upright.

• Place the spacer apparatus mouthpiece at the mouth.

• Breathe at a normal pace and actuate the MDI at the start of inspiration.

• Take a deep breath and hold for 10 seconds; observe that the valve opened during inhalation.

Other usage tips for inhalers and accessory devices are as follows:

• Read and follow the manufacturer's instructions before use.

• Clean devices according to the manufacturer’s instructions or when the device becomes cloudy or filmy inside.

• After cleaning, allow the device to air-dry completely before the next dose is administered.

• Replace disposable parts to avoid bacterial growth, as recommended by the manufacturer.

• Shake the MDI before using.

• Do not spray 2 actuations of medication into a holding chamber or spacer at one time.

• Note the purchase date of the device on the side of the device with a permanent marker; discard the unit when advised by the package instructions.

The nebulizer transforms liquid medicines into particles (eg, aerosol, mist) breathable through a mouthpiece or mask. A nebulizer kit consists of an air compressor, nebulizer cup, mouthpiece or mask, and measuring device for medication. Instructions for use are as follows:

• Place the nebulizer on a steady surface.

• Assemble the nebulizer apparatus and plug in the power source, as shown in the image below.

• Wash hands.

• Place the medicine in the specified dose in the nebulizer cup and close it.

• Attach the top portion of the nebulizer cup to the mouthpiece or to the mask, as shown in the image below.

  Nebulizer apparatus schematic.

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• Connect the bottom of the nebulizer cup with tubing to the air compressor.

• Activate a gas pressure source (Venturi) at the orifice of the reservoir.

• Instruct the patient to breathe through the mouth with a slow inspiratory flow and occasional deep breath.

• Turn the nebulizer on to test and confirm that a mist is generated.

• Have the patient sit up comfortably straight; if using a mask, secure it in a comfortable position, as shown in the image below.

  Nebulizer mouthpiece positioning.

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• During treatment, periodically monitor the patient for adverse effects and response.

• Stop the nebulizer once it starts to sputter.

Other usage tips for the nebulizer are as follows:

• Follow the package instructions of the nebulizer unit.

• Order replacement supplies early so that they are available when needed; replace disposable parts (eg, nebulizer cup), tubing, and filters according to the manufacturer’s instructions.

• Clean the nebulizer as instructed by the package instructions after every use to prevent bacterial growth; throw away nebulizer tubing that is cloudy or retains moisture.

• When not using the nebulizer, store it in a clean, dry, and dust-free location.

• Note the treatment start date on a daily symptom diary (eg, Asthma Tracker) for future reference.

• Always use a mask or mouthpiece with nebulizer treatment.

• Purchase nebulizer supplies and units such as masks that can be used for infants and toddlers in a reclined position (eg, sleeping).

• With battery-operated nebulizers, keep the nebulizer batteries charged or have replacement batteries on hand.

• Use only those unit dose vials or other liquid medications made specifically for nebulizers and approved by the US Food and Drug Administration (FDA).

Complications

Bacterial contamination of a spacer device or nebulizer tubing and hand unit can occur. To help prevent this contamination, these items must be periodically cleaned with detergent.

Each device is unique, and new devices are constantly coming onto the market. Patients must fully understand how to operate, maintain, and administer their medication. ^{[3, 4, 28]} Various patient-oriented Web sites provide good resources that explain the use of inhalers.

A systematic review found that inhaler technique among children with asthma was generally poor; however, educating children about the proper use of inhalation devices was associated with improvements in technique. ^[29]

For patient education information, see the Asthma Treatment Guide.