How Do We Achieve Optimal Asthma Control? Role of Nebulised steroids in Management of Asthma BY MAYSA SHARAF ELDIN PROFESSOR OF PULMONARY MEDICINE CAIRO UNIVERISITY

Why do we care about asthma control? What do we mean by asthma control? Inhalation Therapy Prof. Maysa Sharaf El Din

Why do we care about asthma control? Prof. Maysa Sharaf El Din

Burden of Asthma Asthma is one of the most common chronic diseases worldwide with an estimated 300 million affected individuals Prevalence increasing in many countries, especially in children A major cause of school/work absence GINA 2010

Burden of Asthma Health care expenditures very high Developed economies might expect to spend 1-2 percent of total health care expenditures on asthma. Developing economies likely to face increased demand Poorly controlled asthma is expensive; investment in prevention medication likely to yield cost savings in emergency care GINA 2011

What do we mean by asthma control? Prof. Maysa Sharaf El Din

Clinical Control of Asthma No (or minimal)* daytime symptoms No limitations of activity No nocturnal symptoms No (or minimal) need for rescue medication Normal lung function No exacerbations No emergency visits No treatment-related adverse events All of the above sustained for at least 7 out of 8 weeks * Minimal = twice or less per week GINA 2011

Clinical Control of Asthma How many of our patients actually achieve this? No (or minimal)* daytime symptoms No limitations of activity No nocturnal symptoms No (or minimal) need for rescue medication Normal lung function No exacerbations No emergency visits No treatment-related adverse events All of the above sustained for at least 7 out of 8 weeks * Minimal = twice or less per week Asthma without Asthma GINA 2011

Factors Affecting Inhaled Drug Delivery and Deposition - Geometry of the respiratory tract - Inspiratory flow - Time in the airway (breath hold) - Particle diameter and density There are number of factors that affect drug deposition in the the airways. These include: Geometry of the respiratory tract Airflow Particle diameter and size Time in the airway (breath hold) Prof. Maysa Sharaf El Din 9

What we know: Particle Size > 5 Particle size (microns) Regional deposition Efficacy Safety Mouth / oesophageal region No clinical effect Absorption from GIT if swallowed All inhaled methods ( MDI & DPI ) Compliance, adequate technique 75% - 93% of patients on traditional press-and-breathe inhalers use improper technique Even after retraining, up to 50% revert to incorrect techniques 2 – 5 Upper / central airways Clinical effect Subsequent absorption from lung < 2 Peripheral airways / alveoli Some local clinical effect High systemic absorption Prof. Maysa Sharaf El Din 10

Factors affecting drug delivery with nebulised therapy 1. Device-related factors Airflow Droplet size Nebulisation time and volume 2. Drug-related factors The shape and size of drug particles water solubility The viscosity and surface tension of the formulation 3. Patient-related factors Breathing patterns inspiratory flow rate Prof. Maysa Sharaf El Din

Clinical Profile: Who Are the Ideal Patients for Nebulized Therapy? Patients inadequately controlled and unable to achieve symptomatic relief with MDI/DPI therapy Patients with cognitive impairment Patients unable to use MDI/DPI devices appropriately (eg, patients with arthritis, peripheral neuropathy) Home health care patients Prof. Maysa Sharaf El Din 12

Advantages of Nebulizers Any age Easy to teach and use Patient coordination not required preferred inhalation device in infants and for acute Rx in ERs and hospital High drug doses possible Can be used with supplemental oxygen No propellant required Prof. Maysa Sharaf El Din 13

Types of nebulizers Jet nebulizer 2. Ultrasonic nebulizer Driven by compressed air. The smaller droplets leave the nebuliser as a fine mist.The larger droplets fall by gravity and returned to the reservoir 2. Ultrasonic nebulizer The aerosol is created by a rapid vibrations. Ultrasonic nebulisers should not be used to deliver suspensions 3. Mesh nebulizer Liquid or drug suspension is pushed through a fine static mesh. There is no recycling into the reservoir of inappropriately sized droplets Prof. Maysa Sharaf El Din

Jet and Ultrasonic Nebulizers Cools during operation Small aerosol particle size Less expensive More noise ULTRASONIC Heats up during operation Larger aerosol particle More expensive Less noise Prof. Maysa Sharaf El Din 15

New Generation Nebulizers: Vibrating Mesh or Plate Nebulizers MicroAIR U22 Pari e-flow www.aerogen.com/theproducts.htm www.omron-healthcare.com www.eflow.pari.de/200/index.html 16

Advantages of New Vibrating Mesh or Plate Nebulizers Simple, compact, silent Do not require propellants or a compressor system Portable, battery operated, designed for use by ambulatory patients High fine particle fraction Highly efficient delivery of aerosols to lower respiratory tract Only negligible volume of drug solution left in device Low aerosol velocity   throat deposition Prof. Maysa Sharaf El Din 17

Limitations of Vibrating Plate/Mesh Devices Cost higher than jet nebulizers Need for regular cleaning to prevent blockage of minute apertures with drug particles (especially with suspensions) Batteries need to be replaced periodically Need to reduce drug dose/volume of solution because of higher efficiency of drug delivery in order to prevent “overdosing” Prof. Maysa Sharaf El Din 18

Adaptive Aerosol Delivery (AAD) “Smart nebulizers” Principle: delivery of precise and reproducible amounts of drug adapted to the breathing pattern during part of inspiration Benefit - improvement of efficacy and compliance Prodose AAD System 19

Partially uncontrolled Uncontrolled Hoda is 45 years old female patient. She has long-term asthma. She is known case of Diabetes. Her current treatment is ICS+LABA plus SABA when needed. She has symptoms which impair ability to sleep and perform daily activities with persistent cough, wheezing and chest tightness several days each week Q: Is her asthma Well controlled Partially uncontrolled Uncontrolled

Partially uncontrolled Uncontrolled Hoda is 45 years old female patient. She has long-term asthma. She is known case of Diabetes. Her current treatment is ICS+LABA plus SABA when needed. She has symptoms which impair ability to sleep and perform daily activities with persistent cough, wheezing and chest tightness several days each week Q: Is her asthma Well controlled Partially uncontrolled Uncontrolled

Levels of Asthma Control Characteristic Controlled (All of the following) Partly controlled (Any present in any week) Uncontrolled Daytime symptoms None (2 or less / week) More than twice / week 3 or more features of partly controlled asthma present in any week Limitations of activities None Any Nocturnal symptoms / awakening Need for rescue / “reliever” treatment More than twice / week Lung function (PEF or FEV1) Normal < 80% predicted or personal best (if known) on any day Exacerbation One or more / year 1 in any week GINA 2011

What is your further management? Increase dose of ICS Add Theophylline Start Antibiotics Oral steroids

What is your further management? Increase dose of ICS Add Theophylline Start Antibiotics Oral steroids

Step 4 – Reliever medication plus two or more controllers Selection of treatment at Step 4 depends on prior selections at Steps 2 and 3 Where possible, patients not controlled on Step 3 treatments should be referred to a health professional with expertise in the management of asthma Medium- or high-dose inhaled glucocorticosteroid combined with a long-acting inhaled β2-agonist (Evidence A) Medium- or high-dose inhaled glucocorticosteroid combined with leukotriene modifiers (Evidence A) Low-dose sustained-release theophylline added to medium- or high-dose inhaled glucocorticosteroid combined with a long-acting inhaled β2-agonist (Evidence B) 2009 (Evidence A)

She increased her inhaled steroid from 2 to 4 inhalations twice daily, but noted no improvement. She found herself needing to use her ventolin inhaler 4-5 times per day. After a sleepless night of cough and chest congestion, she sought help at her local hospital In the ED she appeared in moderate distress. She had laboured breathing at 28 breaths/min, with a markedly prolonged expiratory phase. She was using her accessory muscles of respiration. Her blood pressure was 120/70 mm Hg with 20 mm Hg paradoxical pulse. Her heart rate was 112 beats/minute. Chest examination revealed musical inspiratory and expiratory wheezes throughout all lung fields.

What is the required treatment for her in hospital? Nebulised steroids Oxygen therapy IV Theophylline Nebulized SAMA All of above None of the above

What is the required treatment for her in hospital? Nebulised steroids Oxygen therapy IV Theophylline Nebulized SAMA All of above None of the above

Oral steroids Nebulized steroids ICS No steroids Over the next 2-3 days she progressively improved, and is now ready for home discharge. To prevent relapse after hospital or ER discharge , would you recommend : Oral steroids Nebulized steroids ICS No steroids

Oral steroids Nebulized steroids ICS No steroids Over the next 2-3 days she progressively improved, and is now ready for discharge home. To prevent relapse after hospital or ER discharge , would you recommend : Oral steroids Nebulized steroids ICS No steroids

How do you classify her acute asthma? Near-fatal asthma Life threatening asthma Acute severe asthma Moderate asthma exacerbation Brittle asthma

How do you classify her acute asthma? Near-fatal asthma Life threatening asthma Acute severe asthma Moderate asthma exacerbation Brittle asthma

Levels of severity of acute asthma Life threatening asthma : altered conscious level, Exhaustion, Arrhythmia Hypotension, Cyanosis, Silent chest, Poor respiratory effort. Near-fatal asthma : Hypoxemia SpO2 <92%, PaO2<60 mmHg and/or Raised PaCO2 requiring MV with raised inflation pressures. Acute Severe Asthma : Any one of: unable to complete 1 sentences in 1 breath, respiratory rate ≥25/min, heart rate ≥110/min, PEF 33-50% best or predicted Moderate asthma exacerbation: Increasing symptoms, PEF >50-75% best or predicted no features of acute severe asthma Brittle Asthma : Type 1: wide PEF variability despite intense therapy (>40% diurnal variation for >50% of time over a period >150 days) Type 2: sudden severe attacks on a background of apparently well controlled asthma British Thoracic Society Guidelines (BTS) 2009

NOTES Prof. Maysa Sharaf El Din

Management of Acute Asthma (Evidence-Based) Instructions for correct use of Nebulizer: Budisonide should be administered via Jet Nebulizer with a mouthpiece or suitable facemask. Ultrasonic nebulizers are not suitable & therefore dis-recommended. Nebulizer should be connected to an air compressor with an adequate airflow (5 – 8 l/min). Fill volume should be 2 – 4 ml. Instructions for correct use of Nebulizer: 4. Budisonide Nebulising Suspension can be mixed with 0.9% saline & nebulizer solutions of: Terbutaline Salbutamol Sodium Cromoglycate Ipratropium Fenoterol Acetylcysteine Management of Acute Asthma (Evidence-Based) Regular bronchodilators including ipratropium bromide. (Level A). Oxygen (Controlled) (Level A). Corticosteroids (Level A). No role for routine antibiotics, rehydration (Level A). Magnesium for more severe attacks (Level A). Prof. Maysa Sharaf El Din

Reactivated Esterification of budesonide Cell Nucleus GC-receptor Budesonide Budesonide Prolonged duration of action esterifi- cation lipolysis Increased airway selectivity Budesonide esters INACTIVE! 12. Intracellular esterification of budesonide. After entering the cell, inhaled budesonide (like other GCSs) binds to the glucocorticosteroid (GC) receptor, and the resulting complex translocates to the cell nucleus. However, surplus budesonide also forms esters with long-chain fatty acids, resulting in the formation of a depot of budesonide esters within the cell (Miller-Larsson et al, 1998; Thorsson et al, 1998). These conjugates are inactive, but as the concentration of free budesonide in the cell decreases, free budesonide is released from them under the influence of lipases (Miller-Larsson et al, 1998; Wieslander et al, 1997). Miller-Larsson et al. 1998 and Wieslander et al. 1997

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Disadvantages of Jet Nebulizers Bulky, expensive (equipment/medication) Require A/C for compressor (lack of portability) Require frequent cleaning Time consuming to dispense medication Wide variability in output characteristics Nebulizer brand Fill volume Flow rate of compressed gas 38