Inhalers in Pediatric Asthma

Dr. KISHORE CHANDKI Kids Care Clinic, Indore (M.P.) INDIA

Asthma in Children
With 30 million asthmatics in the country, India constitutes 10% of the world asthmatics Most common chronic disease of childhood Up to 20% of children affected in various geographical areas Up to one-fourth of the children in the pre-school age in oneprewheezers. Delhi are recurrent wheezers. [Times of India, Dec 18, 2004] No age is exempt from asthma & it can even start early in infancy. In most children, asthma develops before age 5 years, years, and, in more than half, asthma develops before age 3 years

Asthma in Children
Unfortunately, prevalence is increasing in India Fortunately, asthma can be effectively treated & most patients can achieve good control of their disease Most in India are either unaware, undiagnosed or are subsub-optimally treated for asthma. This is despite India having the latest, most effective and extremely affordable inhaled medicines to control asthma The most effective asthma treatment Inhalation Therapy is available in India at a price as low as Rs. 4 to Rs. 6 per day which means that a years supply of medicine is less than the cost of 1 nights stay at the hospital!

What is Asthma?
Asthma is a chronic inflammatory disorder of the inflammatory airways. Chronically inflamed airways are hyperresponsive; hyperresponsive; they become obstructed & airflow is limited (by bronchoconstriction, mucus plugs, & increased inflammation) when airways are exposed to various risk factors Asthma attacks (or exacerbations) are episodic, but airway inflammation is chronically present A stepwise approach to pharmacologic treatment to achieve & maintain control of asthma should take into account the safety of treatment, potential for adverse effects, & the cost of treatment required to achieve control Asthma is not a cause for shame. Olympic athletes, shame. famous leaders, other celebrities, & ordinary people live successful lives with asthma

Components of Asthma
Asthma Triggers Allergens Smooth Muscle Dysfunction
Hypertrophy Hyperplasia Inflammatory Mediator Release

Exercise

Irritants

Viruses

Weather Inflammation
Mucus Secretion

Edema Impaired Ciliary Function

Architectural Changes

Epithelial Damage

Bronchial Constriction

Bronchial Hyperreactivity

Inflammatory Cell Infiltration

Symptoms Exacerbations
Adapted from Creticos. Adv Stud Med. 2002;2(14):499-503

Consequences of Inflammation in Asthma

Stimulus
(Antigen, virus, pollutant, occupational agent)

Altered airway physiology o Airflow obstruction

Acute Inflammation Resolution

o Airway dysfunction

Chronic Inflammation Injury Repair

Permanently altered lung function

Remodeling (fixed changes in the structure of airway)

Triggers for acute exacerbation Bhave et al

5% 1%

Viral infection

14 %

Cold drinks/icecreams
37%

Food item

Dust exposure
11%

Change of season

7%

Picnics/camps

8% 8%

9%

Physical stress

N = 1050

Emotional stress

Outcome of Wheezers
Among infants, 20% have wheezing with only URIs, & 60% no longer have wheezing by age 6 years Children who have asthma (recurrent symptoms continuing at age 6 y) have airway reactivity later in childhood Children with mild asthma who are asymptomatic between attacks are likely to improve and be symptomsymptomfree later in life Children with asthma appear to have less severe symptoms as they enter adolescence, but half of these children continue to have asthma. Asthma has a tendency to remit during puberty, with a somewhat earlier remission in girls. However, compared with men, women have more AHR

Inhalational Therapy in Pediatric Asthma

Inhalation: cornerstone of asthma treatment Not very popular among lay man because of some misconceptions Although asthma can be well controlled by highly effective anti-inflammatory therapy (mainly ICS) in antimajority, optimal control is not achieved in 50% of patients in daily practice There is a confusing array of inhaler devices & drug/device combinations available and it can be difficult for a clinician to make informed prescribing decisions about all the possible permutations

Inhalational Therapy: Advantages

Aerosol doses are generally smaller than systemic doses; e.g., oral Salbutamol is 2 to 4 mg; inhaled 0.2 mg (MDI) to 2.5 mg (Nebulized) Onset of effect with inhaled drugs is faster than with oral dosing; e.g., oral albuterol is 30 min; inhaled albuterol is ~ 5 min Drug is delivered directly to the target organ (lung), with minimal systemic exposure Systemic side effects are less frequent and severe with inhalation compared to systemic delivery (injection, oral); e.g., less muscle tremor, tachycardia with 2-agonists; 2lower HPA suppression with corticosteroids Inhaled drug therapy is less painful and relatively comfortable

Inhalational Therapy: Disadvantages

Lung deposition is a relatively low fraction of the total aerosol dose A number of variables (correct breathing pattern, use of device) can affect lung deposition and dose reproducibility Difficulty coordinating hand action and inhalation with MDIs Lack of knowledge of correct or optimal use of aerosol devices by patients and clinicians The number and variability of device types confuses patients and clinicians Lack of standardized technical information on inhalers for clinicians

Inhalant Drugs: List

Bronchodilators Arformoterol Bitolterol Epinephrine Formoterol Ipratropium Isoetharine Isoproterenol Levalbuterol Metaproterenol Pirbuterol Procaterol Racepinephrine (racemic epinephrine) Salbutamol Salmeterol Terbutaline Tiotropium AntiAnti-inflammatory Beclomethasone Budesonide Ciclesonide Cromolyn Flunisolide Fluticasone Dexamethasone Fluticasone Mometasone Nedocromil Triamcinolone Antimicrobials Pentamidine Ribavirin Tobramycin Zanamivir Miscellaneous Aromatic ammonia Dornase alfa Glutathione Insulin Methacholine Nicotine Sodium chloride Mucolytics Ambroxol N-acetyl cysteine

Inhalant Drugs: Effects

Asthma Treatment: Evolution

Evolution of Asthma Paradigms

Symptoms

Bronchial Hyperreactivity

Fixed Obstruction

Relieve Symptoms

Prevent Symptoms Prevent Attacks

Prevent Symptoms Prevent Attacks Prevent Remodeling

Therapy for Chronic Asthma in Children

Acute relief from symptoms Anti-inflammatory Sustained bronchodilator Unproven anti-inflammatory

Relievers

Preventers

Controllers

SABA

PRN basis

ICS Chromones Na Cromoglycate Nedocromil Na SR Theophyllines Leukotriene antagonists

LABA

Anticholinergic Adjuncts Ipratropium

Slow release xanthines

Xanthine: Short Acting Aminophylline

Leukotriene antagonists

Adrenaline/Epi

Immunomodulators: Omalizumab (anti-IgE)

Oral short acting 2 agonists & xanthines: not for maintenance Tx Other drugs: oral steroids, H1 antihistamines

Asthma Classification & Management

Levels of Asthma Control > 5 yrs

GINA 2011

*Any exacerbation should prompt review of maintenance treatment to ensure that is adequate By definition, an exacerbation in any week makes that an uncontrolled asthma week Without administration of bronchodilator, lung function is not a reliable test for children 5 years & younger

Levels of Asthma Control 5 yrs

Characteristic Controlled
(All of the following)

GINA 2009

Partly Controlled
(Any measure present in any week)

Uncontrolled
(3 or more of features of partly controlled asthma in any week)

Daytime symptoms:
wheezing, cough, difficult breathing

None
(less than twice/week, typically for short periods on the order of minutes and rapidly relieved by use of a rapid acting bronchodilator)

More than twice/week

(typically for short periods on the order of minutes and rapidly relieved by use of a rapid-acting bronchodilator)

More than twice a week (typically last

minutes or hours or recur, but partially or fully relieved with rapidacting bronchodilator)

Limitations of activities

None
(child is fully active, plays and runs without limitations or symptoms)

Any
(may cough, wheeze, or have difficulty breathing during exercise, vigorous play, or laughing)

Any

Nocturnal symptoms/awa kening Need for reliever/rescue Tx

None
(including no nocturnal coughing during sleep)

Any
(typically coughs during sleep or wakes with cough, wheezing, and/or difficult breathing)

Any

2 days/week

>2 days/week

>2 days/week

Management approach: Children > 5 years & Adults

Management approach: Children 5 years GINA 2009

Controller: None

Controller: Low dose ICS*

Controller: Double lowDose ICS*

LT modifier

Low dose ICS + LT Modifier

Reliever: Rapid acting 2 agonist prn

Partly Controlled Uncontrolled or Partly Controlled on low dose ICS

When asthma Is controlled: Reduce therapy Monitor

Controlled

Education, Environmental Control, As needed rapid-acting 2 agonist

*Preferred

Stepping Up: Inhalation therapy

When asthma is NOT controlled with: Rapid onset, short acting or LABA bronchodilators Repeated dosing with bronchodilators in this class provides temporary relief until the cause of the days signals the need for review and possible increase of controller therapy Inhaled corticosteroids Temporarily doubling the dose of IGCS has not been demonstrated to effective and is no longer recommended. A fourfold or greater increase has been demonstrated to be equivalent to a short course of Oral GCS Combination of ICS & LABA In a single inhaler both as a controller and a reliever is effective in maintaining a high level of asthma control and reduces exacerbation requiring systemic GCS and hospitalization

Stopping Inhalation therapy

When control is achieved with
Low dose ICS switch to once daily dosing reduce by 50% after 3 mo Mod to high dose ICS ICS + LABA

Reduce ICS by 50% Bring ICS to lowest dose Omit LABA

ICS + Other

Same as above

Stop when no symptoms for one year

Equipotent Daily Doses of ICS: Age > 5 years/Adults

Equipotent Daily Doses of ICS

Drug (g) Beclomethasone Budesonide Budesonide-Neb Inhalation Suspension Ciclesonide Flunisolide Fluticasone Mometasone furoate Triamcinolone acetonide Low Daily Dose >5 y 5y 200-500 200-600 100-200 100-200 250-500 Medium Daily Dose >5 y 5y >500-1000 600-1000 >200-400 High Daily Dose >5y 5y >1000 >400 >400 >1000

>200-400 >1000 >500-1000

80 160 500-1000 100-250 200-400

80-160 500-750 100-200 ?100-200

>160-320

>160-320

>320-1280

>320 >1250 >500 >400 >1200

>1000-2000 >750-1250 >2000 >250-500 > 400-800 >200-500 >200-400 >500 >800-1200

400-1000 ? 400-800

>1000-2000 >800-1200 >2000

Combination Inhalers
    Steroid/LABA Can improve compliance Useful when asthma stable Lack of flexibility to or dose

Multidosing
 Multiple puffs (up to 10) of a short-acting 2 agonist via shorta spacer device is as effective as nebulised  Children (& adults) with mild & moderate exacerbation of asthma should be treated by bronchodilator given from a MDI + spacer with doses titrated according to clinical response

Inhalational Therapy: Devices

Aerosol devices include: include:
Metered-dose inhaler (MDI) MeteredPressurized Metered Dose Inhaler (pMDI) Breath-activated metered-dose inhaler BreathmeteredMetered-dose inhaler with spacer MeteredDry powder inhaler (DPI) e.g. Rotacaps Nebulizer

Metered Dose Inhalers (MDI)

Uses chemical propellants (hydro-fuoroalkane (hydroinstead of CFC) to deliver medication dose to lungs
Salbutamol (Asthalin, Ventorlin) Levosalbutamol (Levolin) Salmeterol (Serobid) Terbutaline (Bricanyl) Ipratropium (Ipravent) Triotropium (Tiova) Combinations (Duolin, Aerocort, Seroflo)

Metered Dose Inhalers (MDI)

Reliever bronchodilators (usually blue) Long acting beta 2 agonists (Always green)

Inhaled steroids (usually brown/orange)

MDI Inhalers
Advantages
Portable, compact Short treatment time Reproducible dose emitted per actuation Most medications are available in this form

Disadvantages
HandHand-breathing coordination & technique important High oropharyngeal impaction without spacer Failure to shake can alter drug dose Foreign body aspiration from debris-filled debrismouthpiece No dose counter

Dry Powder Inhalers (DPIs)

 Rotahaler  Diskhaler  Diskus

DPI: Rotahaler
Advantages
Small and portable BuiltBuilt-in dose counter PropellantPropellant-free BreathBreath-actuated (drug comes when patient breaths in) Short preparation and administration time

Disadvantages
Dependence on patients inspiratory flow Patients less aware of delivered dose Relatively high oropharyngeal impaction can occur Moisture sensitive Limited range of drugs More expensive than MDI

Spacers or holding chambers



Now recommended for administration of all MDI medications

Spacers
Advantages
Less/No coordination required Improved delivery of drug to lower airways May breathe in & out several times to receive complete dose Faster delivery than nebulizer & less expensive Reduced oropharyngeal drug impaction & loss

Disadvantages
Large, cumbersome than MDI alone Expensive wrt MDI alone Cleaning required Some assembly may be needed Patient errors include firing multiple puffs into chamber prior to inhaling, or delay between actuation and inhalation

Spacers
Steroids from a MDI must always be prescribed with a spacer to improve drug delivery and diminish side-effects sideSmaller volume (250-300 ml) are suitable for children < 5 years and (250larger volume > 500 ml) for older children Should be washed weekly. To reduce the static electricity in plastic weekly. spacers the spacer should be washed with a liquid detergent, not rinsed in water, and left to drip-dry overnight dripIf commercially available spacers are not available a 500 ml plastic bottle can be used as a spacer. A hole to fit the MDI is cut or melted into the bottom of the bottle using the hot wire technique. Polystyrene cups are not efficient spacers One puff at a time should be actuated into the spacer and the child should breathe 4-5 times before the next actuation. After inhalation 4rinsed. of ICS, the mouth should be rinsed. If a spacer with a facemask is used it should be applied tightly to the face. The face should be washed after corticosteroid inhalation to prevent skin changes (spider nevi, atrophy)

Nebulizers
Nebulizers are principally used for
Children (<5 years) and adults (<55 years) who have difficulty coordinating the use of MDIs and DPIs By patients with severe asthma or chronic obstructive pulmonary disease (COPD)  In the emergency room for acute episodes of bronchospasm

Nebulizers
Advantages
Use of passive breathing: Any age Easy to teach & use Patient coordination not required High drug doses possible, Many drugs Can be used with supplemental O2 Mixtures (>1 drug), if drugs are compatible

Disadvantages
Time intensive Inefficient & cumbersome Equipment and power source required Cleaning required Variability in performance Potential for drug delivery into eyes with mask

How to choose delivery devices for asthma

Nebulizer  Infants & toddlers  Emergency  Poor coordination

Arch Dis Child 2000;82:185-187

Inhalational Drugs: Metabolism

The fate of an inhaled drug. The total amount of drug in the systemic circulation is the sum of the systemic absorption via the lungs and via the GI tract

Inhaler Devices & Drug Delivery

Nebulizer DPI MDI 1 5% 5 10% 5 10%

MDI with Spacer (esp. Steroids) 10 15% Disc DPI Turbuhaler ~15% >30%
Asthma By Consensus, IAP

Inhaler Devices & Drug Delivery

Device & Technique: Concerns

 Up to 50% of patients are unable to use inhaler correctly  Most patients, nurse and doctors are unable to use pMDIs correctly  Patients forget instructions and skills deteriorate over time reassessment and re-education re Need for clear specific training for patients of correct inhaler technique

Barriers to Inhalational Therapy

Fear about steroids Do not like public labeling as asthmatic Fear of addiction Feel pumps reserved for serious or severe attacks or will fail to act Misconception that costly Prefer oral medications Physicians lack of knowledge and time

Inhaled Corticosteroids: FDA-Approvals FDAMometasone DPI Beclomethasone MDI Budesonide DPI Flunisolide MDI Triamcinolone MDI Beclomethasone MDI (HFA) Fluticasone MDI (HFA) Fluticasone/Salmeterol DPI Fluticasone DPI
Budesonide Nebulization

9 10 11 12 13 14 15 16+

Age of Children (Years)

FDA = Food and Drug Administration; DPI = dry-powder inhaler; MDI = metered-dose inhaler; HFA = hydrofluoroalkane

Inhaled Corticosteroids
 Minimal effective dose to control asthma in the patient is always a goal of ICS therapy  In the past, patients were started on medium to high doses of ICS until control is achieved & then step down to the lowest dose that maintains control. The current guidelines recommend starting patients on dosages based upon level of severity and then to titrate up or down based upon responsiveness to therapy  Most patients' symptoms will improve in 12 weeks of 1 therapy & will reach maximum improvement in 48 weeks. 4 Lung function improvement begins in 12 weeks and 1 usually plateaus at 4 weeks but may increase slightly thereafter for 68 weeks. Improvement in bronchial 6 hyperresponsiveness requires 23 weeks and approaches 2 maximum in 13 months but may continue to improve 1 over 1 year

Inhaled Corticosteroids
 Many patients with mild persistent asthma can be oncetherapy, effectively treated with once-daily ICS therapy, usually more effective given in the evening.  Currently, mometasone is the only ICS with approved USUS-FDA labeling to begin therapy once daily & Budesonide has once-daily approved labeling once oncecontrol is established on twice-daily dosing. All other twiceICSs are labeled for twice-daily dosing. twice The newest ICS, ciclesonide (CIC), is used in Europe on a once-daily basis in adults and children, but only has a oncetwicetwice-daily approved indication in adults in the United States. The US pivotal trials for CIC in children 411 4 years old with moderate-to-severe asthma gave oncemoderate-tooncedaily dosing of 40, 80, & 160 g.
Current Opinion in Allergy & Clinical Immunology 2011;11(4):337-344

Common MDI Preparations

Drug: Nebulized Salbutamol Levosalbuta mol Budesonide Fluticasone Ipratropium Availability
Asthalin soln 5 mg/mL, respule 2.5 mg/2.5 mL

Dose
0.15 mg/kg (Min 2.5 mg) as often as 20 min 3, then 0.15-0.3 mg/kg up to 10 mg 0.15q1q1-4h PRN, or up to 0.5 mg/kg/hr by continuous nebulization 0.075 mg/kg (Min 1.25 mg) q20 min 3, then 0.075 0.15 mg/kg up to 5 mg q1-4 h q1PRN, or 0.25 mg/kg/hr continuous nebulization. 0.63 mg = 1.25 mg salbutamol for both efficacy & SE Initiating dose 0.5-1 mg BD, Maintenance 0.50.250.25-0.5 mg BD 1 mg BD 0.5 ml < 1 year, 1 ml >1 year every 20 mins for 3 doses, then every 6-8 hours solution 6-

0.31 mg, 0.63 mg, 1.25 mg/2.5 mL Respules Levolin / Aerozest

Respule 0.5 mg/2 mL, 1 mg/2 mL MDI Bunase 100/200 0.5 mg/2 mL, 2 mg/2 mL Neb respirator solution 0.25 mg/ml, Respule 0.5 mg/2 mL

Common MDI Preparations

Drug Salbutamol Availability
Asthalin /Ventorlin MDI 100 g/dose (DPI 200 g/dose) Levolin/ Aerozest 50 g (DPI 100 g) Budecort/Pulmicort MDI 100/200 g/dose (DPI 100/200/400) Flohale MDI 25/50/125 g/dose (DPI 50/100/250 ) Ipravent MDI 20 g/dose (DPI 40) MDI Aerotrop g (DPI 18g )

Dose
4-8 puff every 20 min 3, then q1-4h. q1Maintenance 1-2 puff q4-6h 1q4Adults: 4-8 puffs every 20 min fo up to 4 4hrs, then same. Before exercise 1-2 puff 5 min before. 1Same puffs as above.

Levosalbuta mol Budesonide Fluticasone Ipratropium Tiotropium

Common MDI Preparations

Drug Salmeterol + Fluticasone
S 25g + F 50/125/250 25g

Availability
Seroflo & Flutrol 50/125/250 (Macleods) Seretide Evohaler 50/125/250 (gsk) Foracort 100/200/400 Budetrol 100/200/ 400 (Macloeds) VentVent-FB FlucortFlucort-F 125/250

Dose
>4 yrs: 2 puffs of 50 g BD (up to 100 BD)

Formoterol + Budesonide
F 6g + B 100/200/400 6g

For maintenance & relief! relief!

Formoterol + Fluticasone Tiotropium + Formoterol

MDI Aerotrop-F (9 + 6 Aerotropg respectively) DPI respectively)

Indications for Referral

The majority of asthmatics can be managed optimally in a primary health care facility, provided the elements of facility, the asthma guidelines are followed. Referral to a specialist is recommended if the goals of management are not achieved, or for following reasons: diagnosis in doubt unstable asthma parents or general practitioners need further support child on high dose ICS (>400 g beclomethasone equivalent per day) oral steroids are required regularly after a life-threatening episode lifefrequent hospitalizations or visits to an emergency room
http://www.pulmonology.co.za/guidelines/asthma%20paed.htm

Take Home Points

 Inhalational therapy remains the mainstay of treatment for asthma in children (Preventers)  Medications can be safely and effectively delivered to children at any age via MDI + spacer  Patient instruction is a key component in determining the device; that a patient can use correctly & in teaching the patient how to properly use the device

Thank you for your time & attention!