JB 9/2001 SF.ppt Conflict of Interest Disclosure Neonatal and - PDF document

JB 9/2001 SF.ppt Conflict of Interest Disclosure Neonatal and Childhood Pulmonary and  Aerogen, Inc Vascular Disease Conference , UCSF Relationships Between Inhaled Aerosol Deposition in the Lungs and Human Lung  Current Support: NHLBI, NIEHS, NSF, NIOSH, Hoffman Physiology in Children and Adults Foundation, BASF Joseph D. Brain Harvard University Saturday, March 11, 2017 Dramatic changes occur in the acinar structure during postnatal lung Neonates & Children vs. Teenagers & Adults development  > O 2 /kg, > surface area/kg, >metabolism, and > activity.  Smaller airways and alveoli Structural alveolation Birth Lung volume ↑  Surface forces contribute more to ”elastic” properties rapid alveolation by the formation of smooth-  More permeable air-blood barrier new septa (secondary septa) from walled primary septa  Maturation of the lungs continues both biochemical and saccular anatomical airspace; Secondary little alveolar septa septation Primary septa 1

JB 9/2001 SF.ppt human birth 1.5~2y ~8years adult rat b. 4d 7d 14d 21d 35d > 90 days Semmler-Behnke et al. , PNAS 2012 What is an Aerosol? Aerosols  A suspension of small solid or liquid particles in a gas (usually air) Particle size determines how aerosols move through air and  Unit of size measurement for respirable aerosols is the where and how they interact with the surfaces they encounter. micrometer (µm) = micron (µ) = 10 -6 m Breathing pattern and lung anatomy also determine deposition of aerosols in the respiratory tract.  Size ranges: Coarse 2.5–10.0 µm Fine < 2.5 µm Ultrafine < 0.1 µm Environmental and pharmacologic aerosols are composed of a range of particle sizes. Monodisperse Same size – unusual Polydisperse A continuous spectrum of sizes 2

JB 9/2001 SF.ppt Aerosols:  Are ubiquitous indoors and outdoors  Cause and aggravate lung disease  Can be an important therapeutic tool Aerosols Can Hurt Neonates and Children Aerosols Can Heal Neonates and Children  Particulate Matter – Indoors, Outdoors, Occupational  Pulmonary Surfactants  Mold, E.G. Stachybotrys chartarum  Antivirals, Antibiotics, e.g. Tobramycin  Passive Tobacco Smoke  Steroids  Airborne Infection: Measles, Tb, Influenza  Bronchodilators  Mucolytic, e.g. Pulmozyme  Neonate and child lungs not only collect toxic particles, they  Anti-proteases, inhibitors of fibrosis or abnormal repair also capture therapeutic aerosols 3

JB 9/2001 SF.ppt Drug Delivery Directly to the Lungs Routes of Exposure and Anatomic Barriers  Rapid delivery to the site of action; the lungs are < 1% of body weight, why waste it. Route Organ Barrier Surface Area Thickness from Typical Daily (m 2 ) Environment to Exposure  High local concentrations where the drug is needed Blood (  m) Dermal Skin Epidermis 1.8 100-1000 Variable,  Minimize dosing of extra-pulmonary sites and thus easily reduced minimize side effects Oral GI Intestinal 1,200 15-40 1.5 kg food Ingestion Tract Epithelium 2 kg water Some particles from  Avoids hepatic uptake and processing. respiratory tract 10-20 m 3 Inhalation Lungs Alveolar 140 0.64  Injections, IV administration, not needed. Moreover if Epithelium (10,000 – 20,000 L) or 15 - 25 kg air the drug is needed on alveolar suraces, the tight Two notable characteristics of the lung: epithelial is avoided • high daily exposure • thin barrier Drug Delivery Through the Lungs Is Possible Advantages of pulmonary delivery of proteins to systemic circulation:  Large surface area—about 150 m 2  Thin barrier—< 1 µm  Few proteases  Avoids first-pass liver clearance  Rapid and efficient transport  Avoids unpleasant injections 4

JB 9/2001 SF.ppt Even Peptide and Protein Hormones Can Be Administered Via the Lungs  Insulin  Somatostatin  Calcitonin  Thyroid stimulating hormone  Parathyroid hormone  α -1-antitrypsin  Human growth hormone Niven RW. Crit Rev Ther Drug Carrier Syst . 1995;12:151-231. Wolff RK, Dorato MA. Crit Rev Toxicol . 1993;23:343-369. Pharmacologic Aerosols: Deposition of Particles The dose of an inhaled aerosolized drug and its anatomic distribution depend on:  aerosol size & concentration, physics  breathing pattern (IMPACTION)  lung anatomy, e.g. acute and chronic changes (asthma, ARDS, PAH)  equipment between the device producing the aerosol and the patient’s airway 5

JB 9/2001 SF.ppt Aerodynamic particle diameter is a determinant of how much and Classification of Particles by Size where particles are deposited in the respiratory tract  Inhalable Coarse Particles, PM >10  m • Can deposit in the nose or mouth (IMPACTION) • Deposited primarily by impaction  Thoracic Coarse Particles, PM 2.5 to 10  m • Can deposit in airways of the lungs • Deposited primarily by impaction and sedimentation  Respirable Particles (fine fraction) PM <2.5  m • Most penetrate beyond the terminal bronchioles and reach the gas exchange region • Deposit there primarily by sedimentation and diffusion Primary mechanism Inertial Impaction  Ultrafine Particles are <0.1  m (also called nanoparticles) of deposition Diffusion Sedimentation • Small fraction by mass but not by number or surface area. • Deposit primarily by diffusion throughout the respiratory tract Now let us review: Effect of Breathing Pattern on Particle Deposition  Increased linear velocity of airflow promotes inertial  Lung anatomy impaction of particles in more proximal airways. When inspiratory flow rates are excessive, there may be  Clearance mechanisms that determine significant losses in the device and oral phatynx. drug retention  An increase in tidal volume leads to deeper penetration by particles, more alveolar deposition.  Lower inspiratory flow rates and increased end tidal breath holds provide more time for diffusion and sedimentation and thus more alveolar deposition. 23 6

JB 9/2001 SF.ppt CONDUCTING AIRWAYS NASOPHARYNX (upper airways) Each clump of alveoli & ducts is called an acinus. Air is filtered, humidified and brought to body Gas exchange occurs here. Temperature in the conducting airways. 7

JB 9/2001 SF.ppt Rates of Particle Clearance Approximate Anatomic Clearance Clearance Half- Region Mechanism time Nasopharynx Mucociliary Minutes Transport Tracheobronchial Mucociliary Minutes to Hours Transport Alveolar Macrophage Hours Phagocytosis Alveolar Macrophage Hours to Months to Dissolution ? Alveolar Macrophage 8

JB 9/2001 SF.ppt Iron Oxide Particles on Respiratory Surfaces of the Lung 3 hours after a 1 hour exposure Arrows indicate macrophages that have taken up iron oxide particles. Austin et al. AJRCCM 195(1):23-31, 2017 Feb. 1 Conclusions:  Give neonates and children clean air.  Take advantage of therapeutic aerosols  Modify devices and delivery strategies as needed.  Early events have long term, life time consequences. Austin et al. AJRCCM 195(1):23-31, 2017 Feb. 1 9