Aerosol Therapy
December 05, 2009, 19:38 Filed in: Physics
Aerosol Therapy
By Donald R. Elton, MD, FCCP
Lexington Pulmonary and Critical Care
Introduction
An aerosol is a suspension of small particles of liquid or solid in a gas. The particles, synthetic or natural, fall within the size range of 0.005 to 50 in diameter. Those that are medically important are less than 3 in diameter. Gravity begins to lose its influence on particles at this mass size. Examples of aerosols include dusts, bacteria, yeast, water, and smoke.
Terminology
Stability of an aerosol is the ability to remain in suspension and maintain its integrity as an aerosol. Stability is dependent upon the size and nature of the particle, the concentration of particles, ambient humidity, and movement of the suspending gas. Instability is the propensity of a suspended particle to remove itself from suspension. For therapeutic aerosols, penetration refers to the depth to which an aerosol particle can be carried by a tidal breath. Deposition refers to the aerosol becoming unstable as particles rain-out or are retained within the respiratory tract. Clearance refers to removal of deposited particles by biologic mechanisms.
Aerosol Generation
There are two main types of aerosol generators in general clinical use today. They are jet nebulizers and ultrasonic nebulizers. A Jet nebulizer works by directing a high flow of gas over a capillary tube that is immersed into the fluid to be nebulized (made into an aerosol). The suction generated at the top of the capillary tube draws fluid up the tube and into the air. Particles of improper size (from a stability stand-point) are frequently directed against a baffle that will encourage rain-out such that the fluid to be nebulized is not wasted by the creation of unstable particles. The particles that rain-out fall back into the fluid reservoir so they can be nebulized again. Many nebulizers have an air intake or venturi to allow the entrainment of room air for dilution of the primary gas, usually oxygen.
An ultrasonic nebulizer consists of a power chamber and a nebulizing chamber. The power chamber includes a ceramic transducer that is described as piezoelectric because is changes electrical energy into pressure energy. The transducer vibrates at a very high frequency (that requires FCC certification) up to about 1.5 mHz. The transducer sits at the bottom of a water filled power chamber. The vibrational energy is transmitted through the water and focused on a flexible diaphragm that vibrates in sympathy. The diaphragm is in contact with the solution to be aerosolized and shakes the solution into particles. At low frequencies, waves are produced that may produce some larger aerosol particles. At high frequencies a fine mist is generated. At low power (amplitude) the particles are produced intermittently as waves break while at higher power settings the particles are liberated continuously. At very high power settings, the chemical makeup of some medications can be disrupted. Ultrasonic nebulizers tend to produce a more consistent particle size than do jet nebulizers and can produce very large volumes of respirable particles with much greater deposition into the lungs. There is some experimental evidence to suggest that long-term use of ultrasonic nebulization can result to disruption of surface tension stability in the lung, perhaps owing to the large amount of fluid deposited into the lungs. Ultrasonic nebulizers are limited in that they cannot aerosolize viscous solutions though this is not a problem clinically.
Aerosol Behavior
Once an aerosol is generated, there is initially quite a variety of particle sizes. As the aerosol ages, however, larger particles aggregate and become unstable, falling out of suspension. This results in a decrease in the size deviation of an aerosol such that the resulting aerosol tends to consist of particles close to 0.1 micron. The depth of penetration of an aerosol particle into the respiratory tract increases as the particle size decreases. The nose will completely filter particles down to 5 to 10 microns in diameter while particles of 1 micron and down can get past the upper airway and into the terminal alveoli. Particles of around 1 micron are retained in alveoli while particles much below this size do not deposit and are exhaled. The rate at which a particle will settle is related to physical properties such as gravity, mass, volume, density, and viscous resistance of air. For particles within the size range of 0.1 to 70 microns, the settling velocity of a particle is proportional to the product of its density and the square of its diameter: Settling rate = Density x Diameter squared. Particles, as they approach 0.1 micron in size, become almost molecular in character and are influenced greatly by the kinetic activity of the suspending gas to a greater extent than gravity. A smaller particle is actually kept in suspension by collisions with adjacent gas molecules as it has a high surface area to mass ratio compared to the larger, more massive particle which is more influenced by gravity. Below a given size (about 0.25 microns) particle deposition/retention is actually increased. Rain-out, or retention, of an aerosol can be facilitated by the inertia of a particle tending to keep the particle moving in a straight line when the flow of inspired air changes direction suddenly. Particles at the edge of a stream of gas are more likely to impact by this mechanism. Particle composition also influences particle stability. A hygroscopic particle will tend in accumulate water vapor and increase the size of itself while other particles might tend to dry out and decrease in size. This mechanism is influenced by the relative humidity of the suspending gas. Ventilatory patterns influence particle deposition and retention. Deposition and retention are directly related to inhaled tidal volume and inversely related to flow rate. These factors are only important in conducting airways and become less important as the inspired gas approaches the alveoli where there is little air movement. Aerosolized particles are cleared from the lung by means of ciliary mucus clearance and by means of pulmonary tissue clearance which is a combination of phagocytosis by macrophages and diffusion and dissolving into tissue fluids.
Medical Aerosols
The two main areas where aerosols are used therapeutically are for humidification therapy and medication delivery. Humidification therapy depends on both the bulk delivery of water or saline solutions to the airways and alveoli as well as the tendency of evaporating particles to increase the relative humidity of the suspending gas. Ultrasonic nebulizers, in particular, are very efficient at delivering large amounts of liquid to the respiratory tract. There is controversy regarding what fluid is best to deliver in this manner. Fluids that are very hypertonic or hypotonic tend to be irritating and lead to coughing and bronchospasm in susceptible individuals. The tonicity of aerosolized fluids also tends to change enroute to the alveoli depending on the humidity of the suspending gas. What starts out as an isotonic solution may be either hypertonic or hypotonic by the time it arrives as the site of deposition. There is also controversy as to whether delivery of liquids to the airways is of any therapeutic value in decreasing the viscosity of or increasing the clearance of mucus.
Medication Delivery
Aerosols are an attractive way to delivery drugs, particularly those whose site of action is the lungs themselves as relatively high doses are delivered to the site of action, sparing high systemic doses that might otherwise cause adverse systemic effects. Unfortunately, there are many problems with using aerosols to deliver medications to include inconsistent dose delivery, inadvertent gastrointestinal delivery, non-uniform distribution of medication in the lungs, and elicitation of bronchospasm. There are even those that theorize that the use of suspending gasses like fluorocarbons might be causing cardiac arrests secondary to cardiac toxicity in some asthmatics.
Dosage delivery
Aerosolized medications are inconsistently delivered to the patient. When one places a given amount of medication in a nebulizer, it is difficult, if not impossible, to predict how much of the medication will actually be delivered to the patient, much less to the site of action in the alveoli where it is theorized that most systemic absorption takes place. The initial site of lost medication is into the room as most aerosols are delivered without the benefit of a closed delivery system. Continuous aerosols such as those delivered by hand held, gas powered nebulizers deliver as much as 2/3 of their output during the patient's exhalation. Of the amount of aerosol produced during inspiration, some still leaks out of the mask or mouthpiece, some rains out in the nose and/or oropharynx and some is actually delivered to the lower airways and lungs. Metered dose inhalers are subject to many of the same limitations and those with very short ejection periods are even more susceptible to asynchronous delivery. Commercially available metered dose inhalers eject about 15cc of gas per actuation. Many text books recommend dosing aerosolized medications the way oral or parenteral medications are dosed, i.e. based on body weight. The problem with this is that patients of different sizes already have different deposition rates. For example, say you have a drug that you'd give to a patient at 1 mg/kg of body weight if given IV. If you are going to use a gas powered continuous nebulizer you would have to use at least 3 times this dose to just get the usual dose directed in the general direction of the patient during inspiration. Since deposition is also minute volume dependent, patients with smaller minute volumes (i.e. pediatric patients) will get less delivery of drug to the lungs than those with larger minute volumes. This means that if you put 2 mg of Terbutaline in a nebulizer for an adult that the same 2 mg of Terbutaline would give a proportionately smaller delivered dose to a newborn. Further complicating the picture is the fact that there is a greater tendency to trap the medication in the upper airway of an infant such that you really have to greatly increase the dose to the nebulizer to treat an infant so it might take 6 mg of Terbutaline in the nebulizer to give an infant the same dose per kg of body weight that an adult would receive with 2 mg of drug in the nebulizer. Basing the amount of medication you place in the nebulizer on the body weight of the patient in a linear fashion will not accurately predict dose delivery to the patient's lungs as they are really inversely related at best. Aerosolized medication dosing is further complicated by the variety of devices used to create the aerosol. There is no simple way to compare doses unless the same nebulizer is used. A case in point is the aerosolization of Pentamidine. There are plenty of recommendations as to what dose of medication to deliver but whatever dose you choose, you must use the same nebulizer used in the study you like or your dose delivery will be different than that which was recommended, perhaps more, perhaps less, perhaps not even close to what you thought you were delivering. Particle Size vs Site of delivery To further complicate matters, the particle size produced by various nebulizers, greatly influences where the aerosol will be deposited and also determines whether it will be retained or simply exhaled. Nebulizers are frequently called efficient if a large percentage of their delivered dose is retained but this usually means that they produce larger particles that are more likely to impact in the upper airway and not be delivered to the alveoli, if indeed, that is the intended target of delivery. In the case of Pentamidine, for example, it is recommended that the Respigard II be used. The retention of the 0.9 particles is only 5.3% meaning that only 5.3% of the dose from the nebulizer is retained. This sounds inefficient and is but if one of the other nebulizers were used then the particle size would result in more of the medication being delivered to airways instead of the alveoli where you want the medicine to go. Rain-out in airways is responsible for at least some of th e complications of therapy and is thus avoided by using a nebulizer producing smaller particles even if much of the aerosol is stable enough to be exhaled again. If one wanted to increase the delivered dose a rebreathing circuit could be used but this would increase the delivered dose to a level greater than what is recommended since the dosage recommendations are made assuming the intentional inefficiency of the the Respigard II.
Intubated patients
Nebulizers and metered dose inhalers have been used with intubated and mechanically ventilated patients. Factors influencing delivery include whether a continuous or inspiration-only nebulizer is used, where the nebulizer is placed in the circuit, and whether a nebulizer or a metered dose inhaler is used. Ventilator settings also influence drug delivery. In general, intubated patients will get less lung deposition and retention than non-intubated patients so dosing has to be adjusted accordingly. So what gives? If you've gotten the idea that it's a joke to pretend that medications can be precisely delivered by aerosol then you have the right idea. Given the many confounding factors influencing drug delivery, the only real ways to sensibly choose a dose is to use secondary indicators such as response to therapy (in the case of bronchodilators) or perhaps measurement of drug levels in serum or urine in the case of Pentamidine. Perhaps it would be more sensible if medications prepared for aerosol delivery were available in standard solutions with no particular dosage ordered and actual dose usage determined strictly on the basis of response.
References
Patel P, Mukai D, Wilson AF: Dose-response effects of two sizes of monodisperse isoproterenol in mild asthma. ARRD (1990 Feb) 141(2): 357-60.
Simonds AK, Newman SP, Johnson MA, Talaee N, Lee CA, Clarke SW: Alveolar targeting of aerosol pentamidine. Toward a rational delivery system. ARRD (1990 Apr) 141(4 Pt 1):827-9.
Kim CS, Trujillo D, Sackner MA: Size aspects of metered-dose inhaler aerosols. ARRD (1985 Jul) 132(1):137-42.
Ilowite JS, Baskin MI, Sheetz MS, Abd AG: Delivered dose and regional distribution of aerosolized pentamidine using different delivery systems. Chest (1991 May) 99(5):1139-44.
Hiller C, Mazumder M, Wilson D, Bone R: Aerodynamic size distribution of metered-dose bronchodilator aerosols. ARRD (1978 Aug) 118(2):311-7.
Peters JA: Humidity and Aerosol Therapy, in Spearman CB, Sheldon RL, Egan DF: Egan's Fundamentals of Respiratory Therapy, 4th edition, The C.V. Mosby Co., 1982.
Hess D, Daugherty A, Simmons M: The Volume of Gas Emitted from Metered Dose Inhalers, abstract, Resp Care, (1991 Nov), 36(11):1320.
ink JB, Cohen NH, Covington J, Mahlmeister MJ: Titration for Optimal Do se Response to Bronchodilators Using MDI and Spacer in Ventilated Adults, abstract, Resp Care, (1991 Nov), 36(11):1321.
Don Elton
Lexington, South Carolina
http://www.lexingtonpulmonary.com
By Donald R. Elton, MD, FCCP
Lexington Pulmonary and Critical Care
Introduction
An aerosol is a suspension of small particles of liquid or solid in a gas. The particles, synthetic or natural, fall within the size range of 0.005 to 50 in diameter. Those that are medically important are less than 3 in diameter. Gravity begins to lose its influence on particles at this mass size. Examples of aerosols include dusts, bacteria, yeast, water, and smoke.
Terminology
Stability of an aerosol is the ability to remain in suspension and maintain its integrity as an aerosol. Stability is dependent upon the size and nature of the particle, the concentration of particles, ambient humidity, and movement of the suspending gas. Instability is the propensity of a suspended particle to remove itself from suspension. For therapeutic aerosols, penetration refers to the depth to which an aerosol particle can be carried by a tidal breath. Deposition refers to the aerosol becoming unstable as particles rain-out or are retained within the respiratory tract. Clearance refers to removal of deposited particles by biologic mechanisms.
Aerosol Generation
There are two main types of aerosol generators in general clinical use today. They are jet nebulizers and ultrasonic nebulizers. A Jet nebulizer works by directing a high flow of gas over a capillary tube that is immersed into the fluid to be nebulized (made into an aerosol). The suction generated at the top of the capillary tube draws fluid up the tube and into the air. Particles of improper size (from a stability stand-point) are frequently directed against a baffle that will encourage rain-out such that the fluid to be nebulized is not wasted by the creation of unstable particles. The particles that rain-out fall back into the fluid reservoir so they can be nebulized again. Many nebulizers have an air intake or venturi to allow the entrainment of room air for dilution of the primary gas, usually oxygen.
An ultrasonic nebulizer consists of a power chamber and a nebulizing chamber. The power chamber includes a ceramic transducer that is described as piezoelectric because is changes electrical energy into pressure energy. The transducer vibrates at a very high frequency (that requires FCC certification) up to about 1.5 mHz. The transducer sits at the bottom of a water filled power chamber. The vibrational energy is transmitted through the water and focused on a flexible diaphragm that vibrates in sympathy. The diaphragm is in contact with the solution to be aerosolized and shakes the solution into particles. At low frequencies, waves are produced that may produce some larger aerosol particles. At high frequencies a fine mist is generated. At low power (amplitude) the particles are produced intermittently as waves break while at higher power settings the particles are liberated continuously. At very high power settings, the chemical makeup of some medications can be disrupted. Ultrasonic nebulizers tend to produce a more consistent particle size than do jet nebulizers and can produce very large volumes of respirable particles with much greater deposition into the lungs. There is some experimental evidence to suggest that long-term use of ultrasonic nebulization can result to disruption of surface tension stability in the lung, perhaps owing to the large amount of fluid deposited into the lungs. Ultrasonic nebulizers are limited in that they cannot aerosolize viscous solutions though this is not a problem clinically.
Aerosol Behavior
Once an aerosol is generated, there is initially quite a variety of particle sizes. As the aerosol ages, however, larger particles aggregate and become unstable, falling out of suspension. This results in a decrease in the size deviation of an aerosol such that the resulting aerosol tends to consist of particles close to 0.1 micron. The depth of penetration of an aerosol particle into the respiratory tract increases as the particle size decreases. The nose will completely filter particles down to 5 to 10 microns in diameter while particles of 1 micron and down can get past the upper airway and into the terminal alveoli. Particles of around 1 micron are retained in alveoli while particles much below this size do not deposit and are exhaled. The rate at which a particle will settle is related to physical properties such as gravity, mass, volume, density, and viscous resistance of air. For particles within the size range of 0.1 to 70 microns, the settling velocity of a particle is proportional to the product of its density and the square of its diameter: Settling rate = Density x Diameter squared. Particles, as they approach 0.1 micron in size, become almost molecular in character and are influenced greatly by the kinetic activity of the suspending gas to a greater extent than gravity. A smaller particle is actually kept in suspension by collisions with adjacent gas molecules as it has a high surface area to mass ratio compared to the larger, more massive particle which is more influenced by gravity. Below a given size (about 0.25 microns) particle deposition/retention is actually increased. Rain-out, or retention, of an aerosol can be facilitated by the inertia of a particle tending to keep the particle moving in a straight line when the flow of inspired air changes direction suddenly. Particles at the edge of a stream of gas are more likely to impact by this mechanism. Particle composition also influences particle stability. A hygroscopic particle will tend in accumulate water vapor and increase the size of itself while other particles might tend to dry out and decrease in size. This mechanism is influenced by the relative humidity of the suspending gas. Ventilatory patterns influence particle deposition and retention. Deposition and retention are directly related to inhaled tidal volume and inversely related to flow rate. These factors are only important in conducting airways and become less important as the inspired gas approaches the alveoli where there is little air movement. Aerosolized particles are cleared from the lung by means of ciliary mucus clearance and by means of pulmonary tissue clearance which is a combination of phagocytosis by macrophages and diffusion and dissolving into tissue fluids.
Medical Aerosols
The two main areas where aerosols are used therapeutically are for humidification therapy and medication delivery. Humidification therapy depends on both the bulk delivery of water or saline solutions to the airways and alveoli as well as the tendency of evaporating particles to increase the relative humidity of the suspending gas. Ultrasonic nebulizers, in particular, are very efficient at delivering large amounts of liquid to the respiratory tract. There is controversy regarding what fluid is best to deliver in this manner. Fluids that are very hypertonic or hypotonic tend to be irritating and lead to coughing and bronchospasm in susceptible individuals. The tonicity of aerosolized fluids also tends to change enroute to the alveoli depending on the humidity of the suspending gas. What starts out as an isotonic solution may be either hypertonic or hypotonic by the time it arrives as the site of deposition. There is also controversy as to whether delivery of liquids to the airways is of any therapeutic value in decreasing the viscosity of or increasing the clearance of mucus.
Medication Delivery
Aerosols are an attractive way to delivery drugs, particularly those whose site of action is the lungs themselves as relatively high doses are delivered to the site of action, sparing high systemic doses that might otherwise cause adverse systemic effects. Unfortunately, there are many problems with using aerosols to deliver medications to include inconsistent dose delivery, inadvertent gastrointestinal delivery, non-uniform distribution of medication in the lungs, and elicitation of bronchospasm. There are even those that theorize that the use of suspending gasses like fluorocarbons might be causing cardiac arrests secondary to cardiac toxicity in some asthmatics.
Dosage delivery
Aerosolized medications are inconsistently delivered to the patient. When one places a given amount of medication in a nebulizer, it is difficult, if not impossible, to predict how much of the medication will actually be delivered to the patient, much less to the site of action in the alveoli where it is theorized that most systemic absorption takes place. The initial site of lost medication is into the room as most aerosols are delivered without the benefit of a closed delivery system. Continuous aerosols such as those delivered by hand held, gas powered nebulizers deliver as much as 2/3 of their output during the patient's exhalation. Of the amount of aerosol produced during inspiration, some still leaks out of the mask or mouthpiece, some rains out in the nose and/or oropharynx and some is actually delivered to the lower airways and lungs. Metered dose inhalers are subject to many of the same limitations and those with very short ejection periods are even more susceptible to asynchronous delivery. Commercially available metered dose inhalers eject about 15cc of gas per actuation. Many text books recommend dosing aerosolized medications the way oral or parenteral medications are dosed, i.e. based on body weight. The problem with this is that patients of different sizes already have different deposition rates. For example, say you have a drug that you'd give to a patient at 1 mg/kg of body weight if given IV. If you are going to use a gas powered continuous nebulizer you would have to use at least 3 times this dose to just get the usual dose directed in the general direction of the patient during inspiration. Since deposition is also minute volume dependent, patients with smaller minute volumes (i.e. pediatric patients) will get less delivery of drug to the lungs than those with larger minute volumes. This means that if you put 2 mg of Terbutaline in a nebulizer for an adult that the same 2 mg of Terbutaline would give a proportionately smaller delivered dose to a newborn. Further complicating the picture is the fact that there is a greater tendency to trap the medication in the upper airway of an infant such that you really have to greatly increase the dose to the nebulizer to treat an infant so it might take 6 mg of Terbutaline in the nebulizer to give an infant the same dose per kg of body weight that an adult would receive with 2 mg of drug in the nebulizer. Basing the amount of medication you place in the nebulizer on the body weight of the patient in a linear fashion will not accurately predict dose delivery to the patient's lungs as they are really inversely related at best. Aerosolized medication dosing is further complicated by the variety of devices used to create the aerosol. There is no simple way to compare doses unless the same nebulizer is used. A case in point is the aerosolization of Pentamidine. There are plenty of recommendations as to what dose of medication to deliver but whatever dose you choose, you must use the same nebulizer used in the study you like or your dose delivery will be different than that which was recommended, perhaps more, perhaps less, perhaps not even close to what you thought you were delivering. Particle Size vs Site of delivery To further complicate matters, the particle size produced by various nebulizers, greatly influences where the aerosol will be deposited and also determines whether it will be retained or simply exhaled. Nebulizers are frequently called efficient if a large percentage of their delivered dose is retained but this usually means that they produce larger particles that are more likely to impact in the upper airway and not be delivered to the alveoli, if indeed, that is the intended target of delivery. In the case of Pentamidine, for example, it is recommended that the Respigard II be used. The retention of the 0.9 particles is only 5.3% meaning that only 5.3% of the dose from the nebulizer is retained. This sounds inefficient and is but if one of the other nebulizers were used then the particle size would result in more of the medication being delivered to airways instead of the alveoli where you want the medicine to go. Rain-out in airways is responsible for at least some of th e complications of therapy and is thus avoided by using a nebulizer producing smaller particles even if much of the aerosol is stable enough to be exhaled again. If one wanted to increase the delivered dose a rebreathing circuit could be used but this would increase the delivered dose to a level greater than what is recommended since the dosage recommendations are made assuming the intentional inefficiency of the the Respigard II.
Intubated patients
Nebulizers and metered dose inhalers have been used with intubated and mechanically ventilated patients. Factors influencing delivery include whether a continuous or inspiration-only nebulizer is used, where the nebulizer is placed in the circuit, and whether a nebulizer or a metered dose inhaler is used. Ventilator settings also influence drug delivery. In general, intubated patients will get less lung deposition and retention than non-intubated patients so dosing has to be adjusted accordingly. So what gives? If you've gotten the idea that it's a joke to pretend that medications can be precisely delivered by aerosol then you have the right idea. Given the many confounding factors influencing drug delivery, the only real ways to sensibly choose a dose is to use secondary indicators such as response to therapy (in the case of bronchodilators) or perhaps measurement of drug levels in serum or urine in the case of Pentamidine. Perhaps it would be more sensible if medications prepared for aerosol delivery were available in standard solutions with no particular dosage ordered and actual dose usage determined strictly on the basis of response.
References
Patel P, Mukai D, Wilson AF: Dose-response effects of two sizes of monodisperse isoproterenol in mild asthma. ARRD (1990 Feb) 141(2): 357-60.
Simonds AK, Newman SP, Johnson MA, Talaee N, Lee CA, Clarke SW: Alveolar targeting of aerosol pentamidine. Toward a rational delivery system. ARRD (1990 Apr) 141(4 Pt 1):827-9.
Kim CS, Trujillo D, Sackner MA: Size aspects of metered-dose inhaler aerosols. ARRD (1985 Jul) 132(1):137-42.
Ilowite JS, Baskin MI, Sheetz MS, Abd AG: Delivered dose and regional distribution of aerosolized pentamidine using different delivery systems. Chest (1991 May) 99(5):1139-44.
Hiller C, Mazumder M, Wilson D, Bone R: Aerodynamic size distribution of metered-dose bronchodilator aerosols. ARRD (1978 Aug) 118(2):311-7.
Peters JA: Humidity and Aerosol Therapy, in Spearman CB, Sheldon RL, Egan DF: Egan's Fundamentals of Respiratory Therapy, 4th edition, The C.V. Mosby Co., 1982.
Hess D, Daugherty A, Simmons M: The Volume of Gas Emitted from Metered Dose Inhalers, abstract, Resp Care, (1991 Nov), 36(11):1320.
ink JB, Cohen NH, Covington J, Mahlmeister MJ: Titration for Optimal Do se Response to Bronchodilators Using MDI and Spacer in Ventilated Adults, abstract, Resp Care, (1991 Nov), 36(11):1321.
Don Elton
Lexington, South Carolina
http://www.lexingtonpulmonary.com