Aerosolized Drug Delivery Devices

Aerosolized Drug Delivery Devices

436 CHAPTER 8.9 suspected and promptly pursued in the diagnostic evaluation. Internal hemorrhage, including hemothorax, hemopericardium, and abdomin...

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CHAPTER 8.9

suspected and promptly pursued in the diagnostic evaluation. Internal hemorrhage, including hemothorax, hemopericardium, and abdominal hemorrhage, may indicate that the diaphragm has been lacerated. Pneumothorax is an uncommon finding with fractured ribs in neonates but may be more likely in older individuals with fractures secondary to blunt trauma. The location of the rib fractures is an important determinant of prognosis. Fractures in the cranioventral portion of the thorax, in proximity to the heart, can cause cardiac laceration and sudden death. Midthoracic rib fractures more frequently cause pulmonary laceration and hemothorax, occasionally with pneumothorax. Fractures in the mid-to-caudal thorax are capable of lacerating the diaphragm and causing secondary lung or abdominal visceral lesions.

Diagnosis The diagnosis of fractured ribs may be obvious when palpable crepitus is associated with an underlying rib. Ancillary diagnostic procedures include ultrasound evaluation and thoracic radiography. In most cases, use of ultrasound can reveal both rib fracture and displacement. Ultrasound is better than radiography for detecting the site of injury and also detects hemothorax, hemopericardium, pneumothorax, or diaphragmatic hernia. A single radiographic view provides an overall assessment of the thorax but ultrasound provides a detailed map.

Treatment The treatment of choice for fractured ribs is rest and confinement for 1 to 3 weeks. This conservative treatment is successful in nearly all cases of uncomplicated rib fracture. Supportive care is indicated for foals in pain, and manual assistance in helping foals to rise and nurse should be pro-

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vided in a manner that avoids direct compression of either the fracture sites or the sternum. Affected foals may be assisted safely by lifting them from sternal recumbency by the elbows. Sedation may be required to prevent flailing or harmful struggling of some patients, and oxygen supplementation via nasal insufflation is indicated for obvious hypoxemia. If severe hypoxemia is present concurrently with a flail thorax, longer-term phenobarbital sedation may be required to maintain the foal in lateral recumbency. In these cases, the intact thoracic wall should be uppermost and occasionally the foal should be allowed to rest on its sternum. Foals that turn over can compress the underlying damaged lung. If the patient is allowed to be ambulatory, the primary concern is cardiac laceration and arrest if cranioventral fractures are further displaced by overactivity. Surgical treatment of rib fractures is uncommon, but in these authors' practice stabilization has been provided by use of dynamic compression plates. The long-term outcome of this procedure currently is being investigated. In cases where rib fractures are responsible for diaphragmatic hernia, surgical repair is essential to a favorable prognosis.

Supplemental Readings Beech J: Equine Respiratory Disorders, Philadelphia, Lea & Febiger, 1991. Mair T, Divers T, Ducharme N: Manual of Equine Gastroenterology, Philadelphia, WB Saunders, 2002. Rantanen NW, McKinnon A: Equine Diagnostic Ultrasonography, pp 591, 624-625, Baltimore, Williams & Wilkins, 1998. Sprayberry KA, Bain IT, Seahorn TL et al: 56 Cases of rib fractures in neonatal foals hospitalized in a referral center intensive care unit from 1997-2001. Proceedings of the 47th Annual Meeting of the American Association of Equine Practitioners, pp 395399,2001.

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Aerosolized Drug Delivery Devices BONNIE R. RUSH Manhattan, Kansas erosolized drug therapy has been the standard treatment approach in human medicine for patients with noninfectious respiratory disease for 20 years. Administration via inhalation improves drug safety and efficacy by reducing the total therapeutic dose, minimizing drug exposure to other body systems, and allowing

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direct delivery of the drug to the lower respiratory tract. In most instances, the response to aerosolized drug administration is more rapid than to systemic drug administration. The equine patient is an ideal candidate for inhalation therapy for several reasons: a highly cooperative nature, obligate nasal breathing, rostrally placed and large

Aerosolized Drug Delivery Devices

nares, slow breathing rate and inspiratory flows, and a spectrum of diseases amenable to topical treatment. However, initially devices such as nebulizers designed for delivery of aerosolized drugs to the lower respiratory tract of horses were cumbersome, expensive, and marginally efficacious. Today, efficient systems for drug delivery are being developed rapidly and inhalation therapy has become increasingly popular for treatment of lower respiratory tract disease. The most important aspects of aerosol administration for horses are efficient pulmonary drug delivery and ease of administration. The disadvantages of the aerosol route of administration include inability to access obstructed airways, high start-up costs, frequency of drug administration, potential for direct airway irritation by some aerosol preparations, respiratory contamination with environmental microorganisms, and contributions to air pollution from propellants. To date, inhalation therapy for horses has focused predominantly on administration of bronchodilating agents and corticosteroid preparations for treatment of recurrent airway obstruction (heaves). Aerosolized antimicrobial agents are under investigation for treatment of bacterial infection of the lower respiratory tract in horses. Bioactive proteins (insulin, antithrombin III, growth hormone) and hormones in aerosol currently being studied in humans may have future application in the horse. Aerosolsare defined as a gas containing finely dispersed solid or liquid suspended particles. The primary determinants of the efficiency of pulmonary deposition of an aerosol preparation include size, shape, viscosity, density, and hygroscopic growth of particles. Most therapeutic aerosols are heterogeneous (heterodispersed), and their aerodynamic behavior is described best by the mass median aerodynamic diameter (MMAD). Aerosol preparations with an MMAD of 1 to 5 microns produce the best therapeutic results in humans and are the target particle size for inhalation therapy in horses. These small particles penetrate deep within the respiratory tract, and particles less than 2 microns can penetrate alveoli. The cross-sectional area (cm-) of the lung increases dramatically at the level of the respiratory zone; therefore the velocity of gas flow during inspiration rapidly decreases at this level. Because the velocity of gas falls rapidly in the region of the terminal bronchioles, small particles sediment out in these airways. Moderate-size particles (5 to 10 microns) frequently settle out by sedimentation in larger more central airways (trachea, bronchi). Large aerosolized particles (> 10 microns) affect the upper respiratory tract via inertial impaction. The majority (90%) of particles below the target size «0.5 microns) are inhaled and exhaled freely and rarely affect the respiratory tract. In addition to particle size, the patient's tidal volume, inhalation and exhalation flow rates, and upper respiratory tract anatomy affect pulmonary drug deposition. Because these physiologic factors, in particular nasal breathing, affect pulmonary drug deposition, equine clinicians cannot extrapolate data generated from human subjects regarding specific drugs or devices to equine patients. Finally, all aerosolized solutions should be isotonic with neutral pH and should not contain chemical irritants such as benzalkonium, ethylenediaminetetraacetic acid (EDTA), chlorbutol, edetic acid, and metabisulfite.

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METERED-DOSE INHALANT SYSTEMS Several devices have been designed for convenient administration of aerosolized drugs formulated in a metereddose inhaler (MDI) cannister to horses with recurrent airway obstruction (Figure 8.9-1). The advantages of an MDI system include rapid administration, consistent exvalve dose delivery, minimal risk of pulmonary contamination with environmental microorganisms, ease of cleaning/maintaining equipment, wide availability, and no requirement for electricity. Pulmonary drug delivery in human patients using MDI devices varies with the specific device, drug preparation, and patient technique. Ideally, the MDI is actuated in early inhalation, during a slow (5second) breath, followed by a lO-second period of breath holding to allow particles to deposit in the lower airway. These conditions are met only in humans. The equine patient inhales over 2 to 3 seconds with no breath hold so that lung deposition is lower. Chlorofluorocarbon (CFC) propellant has been an essential component of MDI drug delivery systems. However, CFCs were recognized to have a depleting effect on the ozone layer in 1985. One CFC molecule is capable of destroying 100,000 molecules of stratospheric ozone and CFC molecules persist in the atmosphere for centuries. Propellants containing CFCsare being phased out of most applications, and newly developed inhalant products are formulated with CFC-free, ozone-friendly solution propellants. Hydrofluoroalkane-134a (HFA) is an inert, nontoxic replacement propellant for CFCs. It is eliminated from the body by ventilation, without evidence of accumulation or metabolism. Because HFA formulations are dissolved in solution, rather than held in suspension, shaking is not necessary between actuations allowing immediate administration of drug with each breath. The efficacyof HFA formulation of some drugs (salbutamol, fenoterol, ipratropium) is equivalent or greater than the CFC preparations. The HFA formulations of beclornethasone, for example, produce a greater total mass of fine drug particles, which improves pulmonary drug deposition and reduces the required daily dose substantially. A twofold to tenfold improvement occurs in pulmonary drug delivery of beclomethasone using an HFA formulation over a CFC formulation depending on the delivery device. Less actuated drug is deposited in the pharynx using an HFA propellant, which reduces the incidence of local and systemic side effects. Because of the greater uniformity of fine particle size, the HFA formulations reduce the need for a spacer in the drug delivery device because spacers are used to enhance fine particles by exclusion of larger particles. The Equine AeroMask (Trudell Medical International, London, Ontario) is the most versatile of the delivery systems because it can be used for administration of aerosolized drugs via MDI devices, nebulization solution, or dry powder inhaler (see Figure 8.9-1, A). This system allows the clinician to administer any drug that is available for human asthma therapy to horses with heaves. Drug is actuated or nebulized into a spacer device designed with a one-way inspiratory valve. The mask must fit snugly around the muzzle to ensure adequate negative inspiratory pressure to facilitate drug delivery. Based on radiolabeling studies, drug delivery to the lower respiratory tract

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Figure 8.9-1 Metered-dose inhalant delivery devices for horses. A, Equine AeroMask fits over the entire muzzle and is equipped with a spacer device (AeroChamber attachment) for use with any metered-dose inhaler available for human inhalant administration. Attachments for nebulization of liquid medication and dry powder inhalant delivery are available, but not shown. H, Equine Aerosol Drug Delivery System fits snugly within the left nostril, is preloaded with one canister of specified drug, and is disposable when the entire canister has been actuated. C, The Equine Haler device fits over the left nostril of the horse and is recommended for use with any metered-dose inhaler designed for human inhalant administration.

through the use of the Equine AeroMask with an MDI is approximately 6% of actuated drug when a CFC propellant is used and approximately 14% of actuated drug when an HFA propellant is used. The large portion of the drug that does not reach the lung is either retained in the spacer or trapped on the surface of the external nares. Drug is distributed uniformly throughout all pulmonary fields. The Equine Aerosol Drug Delivery System (EADDS, developed by 3M Animal Care Products is a novel, handheld device designed for administration of aerosolized drugs in horses (see Figure 8.9-1, B). The EADDS fits snugly into the left nostril of the horse and therefore

avoids a large wastage of drug on the external nares. The operator actuates a puff at the onset of inhalation, denoted by a flow indicator within the device. The operator must pay close attention to the timing of drug delivery, because drug delivered during mid- to late inhalation may reach the tracheal lumen only to be exhaled. The advantage of the EADDS is efficiency of drug delivery. The mean MMAD generated using this system with a CFC propellant is 2.3 :t 2 microns, and approximately 23% of actuated drug is delivered to the lower respiratory tract. The mean MMAD using an HFA propellant is 1.1 microns, and approximately 43% of actuated drug is delivered to the lower respiratory tract in horses.

Aerosolized Drug Delivery Devices

Ventilation imaging using radiolabeled aerosol confirms that drug is deposited in all pulmonary fields with minimal deposition in the nasal cavity, oral pharynx, or trachea. Currently, the EADDS is approved and commercially available only for administration of albuterol sulfate in an HFA propellant (Torpex, Boehringer-Ingleheim Vetmedica, Inc., St. Joseph, Mo.). The device was not designed for administration of interchangeable drugs using human Mlrls. Rather, the device is distributed with a preloaded canister of albuterol sulfate and is designed for disposal after the drug has been dispensed. The Equine Haler (Equine Healthcare APS, Hillerod, Denmark) is a spacer device that fits over the entire left nostril of the horse and is designed for administration of aerosolized drug using any human MOl device (see Figure 8.9-1, C). The mean particle size generated using the Equine Haler is 2.1 microns with a range of 1.1 to 4.7 urn (fluticasone/CFC-free propellant). Drug deposition in the lower respiratory tract was reported to be 8.2 ± 5.2% of the actuated dose with diffuse pulmonary drug delivery that is adequately distributed to the periphery of the lung. As for the AeroMask, nasal trapping and retention in the spacer contributed to drug wastage. Unlike the AeroMask, the Equine Haler can accommodate any size horse without difficulty in creating an airtight seal over the muzzle. Poor pulmonary drug delivery can occur if the administrator does not pay particular attention to align the MOl with the spacer and the spacer apparatus with the nasal passages of the horse during actuation. In all cases, the reaction of the horse to the release of the aerosol, by jerking of the head, or alteration of breathing pattern can detract for lung delivery. In summary, the EADDS system delivers a much greater proportion of drug to the lung but must be inserted into the nostril. The AeroMask and Equine Haler are less efficient because of drug trapping on the nares but have the advantage of being less invasive, and both incorporate spacer-valve combinations that reduce asynchrony of actuation with inspiration and do a better job of selecting fine particles, an important consideration when employing CFC-based MOls.

MECHANICAL NEBULIZERS Ultrasonic nebulizers and jet nebulizers are ozone-friendly delivery systems, used as alternatives to MDI. Ultrasonic nebulizers produce aerosol particles using vibrations of a quartz (piezo-electric) crystal, and particle size is inversely proportional to the operating frequency. High quality ultrasonic nebulizers are required to produce satisfactory particle size. Jet (pneumatic) nebulizers operate by the Venturi effect (dry air compressor) to fragment therapeutic solutions into aerosol particles. The diameter of particles generated by a jet nebulizer is inversely proportional to the airflow, and minimum gas flow rates of 6 to 8 L/min are required to generate suitable particle diameter «5 urn) for pulmonary delivery.Jet nebulizers are readily accessible, inexpensive, and easy to use. The primary disadvantage of jet nebulization is noise generated by the system. Ultrasonic nebulizers are silent; however, they are expensive and fragile. High pressure jet nebulization (Hudson RCI, Temecula, Calif.) using a de-

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livery system developed for horses (Nebul, Agritronix Int, Meux, Belgium) delivers approximately 7% of the drug to the pulmonary system, and ultrasonic nebulization (Ultra-Neb, DeVilbiss, Somerset, N.].) delivers approximately 5% of the drug to the pulmonary system. Deposition of radiolabeled drug into peripheral pulmonary fields using jet nebulization is superior to ultrasonic nebulization. Pulmonary contamination with environmental bacteria and fungi may occur using these aerosol delivery systems; therefore rigorous disinfection of the equipment is required to avoid this complication. Aerosol therapy via jet and ultrasonic nebulization requires an administration time of approximately 10 to 20 minutes, versus less than 2 minutes for many MOl drug dosages.

DRY POWDER INHALANT (DPI) DEVICES Dry powder inhalant devices offer several advantages over nebulization systems, including rapid drug administration, minimal risk of environmental contamination with drug, and no requirement for electricity. The DPIs comprise numerous capsules containing a single dose of drug and a rotor. The rotor of the DPI device is breath-actuated, and the device punctures gelatin capsules containing powdered drug and releases it into a chamber for inhalation by the patient. This system eliminates the need for the operator to synchronize administration with inhalation. The entire dose from an individual dry powder capsule is delivered during a single inhalation; prolonged duration of inspiration and multiple inhalations do not improve pulmonary drug delivery. DPI devices are designed for use by human patients, but have been adapted for drug administration to horses using a specialized facemask (EquiPoudre, Agritronics Int) or a unique adaptor to the Equine AeroMask. The efficiency of drug delivery can be influenced by relative air humidity, airflow, and position. The masks used with DPIs must fit snugly around the muzzle to create adequate inspiratory pressure and flow rates by the horse to ensure sufflcient inhalant emptying rates. The minimum flow rate necessary to trigger the device (60 L/min) is generated easily by healthy and heaves-affected horses. The DPI device and mask must be aligned with the longitudinal axis of the nasal cavities to avoid affecting the powder within the mask or nasal passages. High relative humidity increases retention of drug within the device because of aggregation of powder. If the relative air humidity exceeds 95%, water actually penetrates the DPI and significantly limits drug delivery. Manufacturers recommend administration of DPls under conditions of low relative humidity to minimize the loss of powder within the device. Ipratropium bromide is the most extensively investigated DPI preparation for administration to horses and has demonstrated effective bronchodilation in heaves-affected horses. Numerous devices may be used to deliver aerosolized antiinflammatory and bronchodilator drugs into the equine lung. The equine clinician should be familiar with the technical aspects of aerosolized drug administration because the appropriate drug dosage and frequency of administration for inhalation therapy varies depending on the efficacy of the drug, drug formulation, severity of disease, and efficiencyof

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the delivery device. The quality and quantity of pulmonary drug deposition vary most among the commercially available mechanical nebulizers. The clinician must select a highquality ultrasonic or jet nebulizer to ensure pulmonary drug delivery. The metered-dose inhalant systems produce the most consistent drug delivery given appropriately fitted equipment. Each system has advantages and disadvantages that must be taken into consideration relative to the size, cooperativity, and preferences of the horse and owner.

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Supplemental Readings Ouvivier OH, Votion 0, Vandenput S et al: Review: aerosol therapy in the equine species. Vet] 1997; 154:189-202. Hoffman A: Inhaled medications and bronchodilator use in the horse. Vet Clin North Am Equine Pract 1997; 13(3):519-530. Lavoie JP: Update on equinetherapeutics: inhalation therapy for equine heaves. Comp Cont Educ Pract Vet 2001; 475-477. Votion D,Ghafir Y, Munsters Ket al: Aerosol deposition in equine lungs following ultrasonic nebulisation versus jet aerosol delivery system. Equine Vet] 1997; 29:388-393.

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Use of Aerosolized Bronchodilators and Corticosteroids MELISSA R. MAZAN North Grafton, Massachusetts

n recent years, aerosolized drug therapy in the horse has transitioned from a curiosity to a well established treatment modality. Practitioners and owners alike have recognized the benefit of topical application of bronchodilator and glucocorticoid drugs, thus avoiding the side effects and even toxicities associated with the systemic delivery of these drugs. Although several publications regarding aerosolized drug therapy in the horse have been published in the past 5 years, a dearth of information concerning efficacy, pharmacokinetics, and pharmacodynamics of aerosolized drugs in the horse exists. Often, treatment rests upon extrapolation from discoveries made in the treatment of human asthma or chronic obstructive pulmonary disease (COPD) to the horse. Further complicating the matter is the confusion that still exists concerning various manifestations of inflammatory, nonseptic lower respiratory disease in horses. For the purposes of this discussion, this author will adhere to the recommendations of the recent international workshop on equine chronic airway disease, which recognized two distinct entities: recurrent airway obstruction (RAO, "heaves") and inflammatory airway disease (lAD). Heaves is a familiar disease, whereas lAD is less well defined but encompasses the signs of cough, exercise intolerance, mucus in the airways, and varying degrees of lower airway inflammation in younger horses (see Chapter 8.3: "Inflammatory Airway Diseases: Definitions and Diagnosis in the Performance Horse"). Most practitioners agree that these are two very different clinical entities that clearly demand different treatment recommendations. Nonetheless, it is now generally recognized that inflammation is of vital sig-

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nificance in both conditions. Antiinflammatory treatment is therefore the cornerstone of therapy for each.

TREATMENT STRATEGY The goals of treatment must be clear in order for client, patient, and veterinarian satisfaction, which entails a team approach and acceptance that treatment may be a lifelong issue that may be modified but is unlikely to disappear. Goals in treating RAO should include: (1) immediate relief of the bronchospasm that causes dyspnea, (2) reduction of lower airway inflammation that causes cough and mucus hypersecretion, (3) long-term prevention of episodes of heaves by control of lower airway inflammation and airway obstruction, and (4) return to limited or even full athletic potential. The goals for treatment of nonseptic lAD are similar, as follows: 1. Eliminate bronchoconstriction that impairs performance. 2. Reduce mucus production and airway plugging. 3. Reduce coughing. 4. Reduce airway reactivity. S. Prevent recurrences.

Aerosoltherapy has its place in each of these goals, although systemic corticosteroids are usually necessary for initial reduction of airway inflammation, and environmental control is paramount in long-term control of recurrent airway obstruction (RAO; see Chapter 8.4: "Heaves [Recurrent Airway Obstruction]: Practical Management of Acute Episodes and Prevention of Exacerbations"). To achieve success, the