DEVICE

In 1956, the world's first pressurized MDI was introduced.

Invented by Charles Thiel and two colleagues at Riker

Laboratories.

The idea was born after the daughter of a Riker president

asked "Why can't they put my asthma medicine in a spray

can, like they do hair spray?"

Medihaler pMDI: The original pMDI was equipped with an elongated

mouthpiece, arguably making it the first tube spacer.

Maison 1956

Maison GL, inventor; Riker Laboratories,

Inc., assignee: Aerosol Dispensing

Apparatus. United States patent US

3,001,524. Priority date March 21, 1956;

filed March 5,1957; issued September 26,

1961.

SPACER SYSTEMS

Charles Thiel

Beclomethasone Aerosol by Reservoir Bottle (BARB). Spacer system

comprised a 1.2-L vinegar bottle and facemask with one-way valve.

‘‘I soon tired of gluing my fingers together

—and the following year a plastics

company manufactured the device’’

Freigang 1977

SPACER SYSTEMS

Spacers

(no valves)

Valved holding

Chambers

VHC

PRIMARY OBJECTIVE OF VHC

Minimize the need for coordination between

actuation of pMDI and inhalation hand-lung

coordination (present the aerosol as a standing

cloud of particles)

Ensure that the aerosol particles trail the

inspiratory flow

Reduce the proportion of the dose contained in

large particles and increase the proportion

contained in small particles

Bisphenol A (BPA) is a chemical

that is used to enhance the clarity and

durability of some clear, plastic

products.

The Government of Canada has taken

steps to ban the use of BPA in baby

bottles to reduce newborn and infant

exposure.

Sources of aerosol loss within the spacer

Impaction

Sedimentation time dependent

Electrostatic attraction time dependent

+ - + - + - +

Dead space

Valve insufficiency

Leaking Leaking

Mean net fine-particle-dose electrical charge of aerosols from

commercially available metered-dose inhalers

Barry 1999

Rau 2006

new

detergent-coated

Kwok 2006

ELECTROSTATIC CHARGE

Nebuchamber

Babyhaler

Berg 1998

Dose delivered to filter during 100 consecutive acutations of BUD-

Nebuchamber (nonelectrostatic) and FP-Babyhaler (electrostatic)

Increase 0.8% in day

ELECTROSTATIC CHARGE

Shah 2006

dead space

TV

6 mon

TV

18 mon

Shah 2006

CHALLENGES OF INHALED THERAPIES FOR

YOUNG CHILDREN

Small tidal volume

Small airways

Rapid respiration

Inability to hold breath with inhaled medication

Nose breathing

Aversion to masks

Cognitive ability

Fussiness and crying

Everard 2003

Pattern respiratorio nel bambino

Intranarial position of

the larynx, secure a

continuous airway

from the nose to the

bronchi, therefore

decreases the risk

of pulmonary

contamination by

swallowed matter.

Obligate nasal breathing in the newborn

Xi 2013

GROWTH OF NASAL-LARYNGEAL AIRWAYS IN CHILDREN

Xi 2013

GROWTH OF NASAL-LARYNGEAL AIRWAYS IN

CHILDREN

Inhalation airflow under quiet breathing conditions

Lannefores 2006

Lung volumes and ventilation distribution in healthy and obstructive disease.

Tidal Volume, Total Lung Capacity Functional Residual Capacity

PULMONARY OBSTRUCTION

Changes in FEV1 for three different routes of administration with terbutaline. Greater

clinical effect was seen with drug delivered as inhaled aerosol from a metered-dose

inhaler, compared to similar or larger doses delivered orally or by subcutaneous

injection.

INHALATION

Adults Normal (n=10) FEV1 110 % FEF25-75 103% Mean dose SAL mg 3.28 (2.86–3.88)

Mild (n=10) FEV1 102 % FEF25-75 83% Mean dose SAL mg 3.13 (2.24–3.6)

Severe (n=10) FEV1 49 % FEF25-75 27% Mean dose SAL mg 3.11 (2.54–3.84)

40ug/Kg Salbutamol Ventstream Neb-mouthpiece plasma SAL peak (Cmax) average (Cav) levels 0-5-1-20-30’

Lipworth 1997

Lower plasma concentration 1.31 vs 2,4 and 2.45 ng/ml

Effect of pH on overall albuterol transport in human bronchial epithelial cells.

A decrease in pH is known to change the proton acceptor sites in tight junctions and

decrease the paracellular permeability of cations.

EFFECT OF pH ON ALBUTEROL TRASPORT

Unwalla 2012

Blake 2008

SALBUTAMOL

Salbutamol is a selective β2-adrenoreceptor agonist which ‘relaxes’ airway wall smooth muscle (ASM) irrespective of the mechanism leading to contraction. When inhaled, salbutamol is absorbed into the pulmonary circulation via the alveolar epithelium. There is also evidence to suggest that epithelial cells of conducting airways transport drug from luminal to basal surfaces, that is, into the walls of conducting airways. This suggests that inhaled drug delivery should achieve higher ASM tissue salbutamol concentrations than the intravenous route, on a dose-for-dose basis

SALBUTAMOL

Starkey 2014

Acute airflow obstruction due to airway wall oedema and/or mucus plugging, as might occur in acute bronchiolitis, is not relieved by salbutamol. There is no convincing data to show that infants with recurrent/persistent wheeze benefit from salbutamol Either. Physiological measures of airway obstruction show that salbutamol does reduce airway obstruction in some with recurrent/persistent wheeze. However, most have no response to salbutamol or respond paradoxically. These findings support the presence of functional β2 adrenoreceptors and ASM in the very young. The lack of clinical benefit implies that airflow obstruction in this group of patients is not predominantly due to ASM-induced bronchoconstriction.

SALBUTAMOL IN AIRWAY OBSTRUCTION

Starkey 2014

The bronchodilator action of salbutamol in stable asthma is associated with blood concentrations between 5 and 20 ng/mL for children and adults. Concentration of salbutamol associated with adverse reactions in children is not known. In adults, salbutamol toxicity is associated with blood concentrations greater than 30 ng/mL with a putative lethal level of >160 ng/mL. Very high blood salbutamol concentrations (196–586 ng/mL) have been recorded inchildren receiving intravenous salbutamol and mechanical ventilation for severe asthma.

SALBUTAMOL

Starkey 2014

Usmani 2005

BIGGER MAY BE BETTER: TARGETED Β2-AGONIST THERAPY?

Placebo

Placebo

▲ 30µg of 6µm

♦ pMDI 200µg

■ 30µg of 3 µm

● 30µg of 1.5µm

Δ 15 µg of 6µm

♦ pMDI 200µg

□ 15 µg of 3 µm

○ 15 µg of 1.5µm

• Glucose (rapid dose related) & insulin (inadequate) ↑ BSL

liver muscle ß2 glycogenolysis, hyperinsulinaemia

• potassium ↓ K+ (rapid dose related)

Na/K-ATPase intracellular shift

• lactate ↑ lactic acidosis(dose related)

anaerobic glycolysis in muscle, increased vent demand

• cardiovascular ↓ BP ↑ HR vasodilation skeletal muscle beds + reflex tachycardia, vasodilation pulmonary bed uncouples VQ match tachycardia cardiac ß1, direct inotrope, prolongs QTc interval, cardiac ß2 exacerbated by low K+ low Mg

• increases minute ventilation

• metabolic rate ↑ oxygen consumption ↑ CO2 production

• Imbalance fast- and slow-twitch muscle groups of extremities Tremor

• development of tolerance (reduced ß receptor sensitivity)

SALBUTAMOL SYSTEMIC EFFECTS

Sears 2002 Tobin 2005

SIDE EFFECTS SALBUTAMOL

Rohr 1986

Intravenous (IV) albuterol (250 ug) causes

Decreases in serum potassium (mean 0.6 ±0.3 mEq/L)

Glucose increases (mean 25±15 mg/dl)

Heart rate increases (mean 11±6 beats/mm)

Fowler 2001

Tachicardia

- Direct stimulation cardiac β2-

adrenoceptors

- Indirect activation periphral R

(vasodilatation) and

consequent reflex vagal

withdrawal

Tremor,Hypo-K

- Direct stimulation skeletal muscle

β2-adrenoceptors

(p < 0.001)

26 patients; age >16 years Nebulized salbutamol (2.5 mg) x3 times at every hour.

p = 0.373

Sahan 2012

SIDE EFFECTS SALBUTAMOL

Simulations for children (▪=3 year old,Δ=7 year old, •=12 year old) were developed on 15 mcg/kg (max 250 mcg) bolus dose over 10 min followed by continuous infusion (CI)=1 mcg/kg/min for 3 hours. Simulations for adults (□)

SALBUTAMOL KINTEICS INTRAVENOUS ADMINISTRATION

Starkey 2014

ADULTS CHILDREN

Bolus dose 250 mcg

slow intravenous injection

Less than 2 years age 5 mcg/kg

Over 2 years age

15 mcg/kg; maximum 250 mcg All doses over 5 min

Continuous infusion

3–20 mcg/min 1–5 mcg/kg/min

INTRAVENOUS SALBUTAMOL DOSING RECOMMENDATIONS

BRITISH NATIONAL FORMULARIES FOR CHILDREN AND ADULTS

Bolus + CI Bolus=15 mcg/kg (max 250 mcg) CI=1 mcg/kg/min or 3 mcg/min

Cmax (ng/mL) maximum plasma

concentration

AUC (hr.ng/mL) area under curve (total

systemic exposure)

Adult (70 kg) 7.2 28.0

Child 3 years (14 kg) 68.7 323.8

Child 7 years (23 kg) 74.4 358.7

Child 12 years (39 kg) 79.5 399.7

Starkey 2014

INTRAVENOUS SALBUTAMOL

Neb superior in hypercapnic acute asthma

PEF Pa CO2

**p 0.001

Clinical Index

NEB Group IV Group NEB : 5mg x 2

IV : 0.5mg in 1h

*p 0.05

200

150

100

50

50

40

15

10

5

1 hr 0 0 0 1 hr 1 hr

L/m

in

mm

Hg

**

*

** **

*

Salmeron 1994

N = 47

salbutamol

SABUTAMOL: NEBULIZED VS I.V.

Time response curve for breath alcohol level using Ethylometer (679T) after Salamol ®, inhalation for 16 normal volunteers

O’Conell 2006

ASTHMATICS: TOO DRUNK

2295 children and 614 adults included in 27 trials from emergency room and community settings. Method of delivery of ß2-agonist did not appear to affect hospital admission rates. In adults, the relative risk of admission for spacer versus nebuliser was 0.97 (95% CI 0.63 to 1.49). The relative risk for children was 0.72 (95% CI: 0.47 to 1.09). In children, length of stay in the emergency department was significantly shorter when the spacer was used, with a mean difference of -0.53 hours (95% CI: -0.62 to -0.44 hours). Length of stay in the emergency department for adults was similar for the two delivery methods. PEF and FEV1 were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -6.27% baseline (95% CI: -8.29 to -4.25% baseline).

Authors’ conclusions : MDIwith spacer produced outcomes that were at least equivalent to nebuliser delivery. Spacers may have some advantages compared to nebulisers for children with acute asthma

Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma

Cates 2008 Updated January 2008

Cates 2008

Forest plot of comparison

1 Spacer (chamber) versus Nebuliser (Multiple treatment studies)

outcome: 1.1 Hospital admission

Aeroch

Aeroch

Babyhaler

Aeroch

Babyhaler

Bayhaer/Vol

Volumetic

Aeroch/ACE

Acorn Unkown Ratio

Nevoni Ratio S/N 1/ 4-10

Pulmo-Aide Ratio S/N 1/3.5

Marquest Ratio S/N 1 /4

Ultrasonic Ratio S/N 1/3

Airve 5 Ratio S/N 1/3-1/5

Neb not stated Ratio S/N 1.3/1

Pari Unkown Ratio

Cates 2008

Forest plot of comparison

1 Spacer (chamber) versus Nebuliser (Multiple treatment studies)

outcome: 1.3 Duration in emergency department (hours)

Aeroch

Water bott

Babyhal/Vol

Nevoni Ratio S/N 1/ 4-10

Fleam Unkown Ratio

Airve 5 Ratio S/N 1/3-1/5

Forest plot of comparison

1 Spacer (chamber) versus Nebuliser (Multiple treatment studies)

outcome: 1.9 Rise in pulse rate (% baseline).

Cates 2008

Volumetic

Aeroch

Aeroch

Water bott.

Babyhaler

Aeroch

Bayhaer/Vol

Volumetic

Neb not stated

Acorn Unkown Ratio

Nevoni Ratio S/N 1/ 4-10

Fleam Unkown Ratio

Pulmo-Aide Ratio S/N 1/3.5

Marquest Ratio S/N 1/4

Airve 5 Ratio S/N 1/3-1/5

Neb not stated Ratio S/N 1.3/1

Mazhar 2006

MDI + VHC Volumetic- treated

5x100 µg SAL

NEB Sidestream-Respironics

5000 µg in 4 ml

I vitro emittted dose (µg) 237.2 (8.8) 1649.5 (49.1)

% fine particle fraction 44.0 (2.4) 80.1 (2.0)

Fine particle dose 104.1 (3.9) 1321.2 (39.3)

MMAD (µm) 2.8 (0.1) 2.2 (0.4)

Geometric standard deviation 1.7 (0.1) 3.45 (1.1)

19 asthmatics (12 ) mean (SD) age 53.7 (17.1) 2-4 days after exacerbation SAL urine 30’, SAL urine 24 (HPLC); lung function

Mazhar 2006

MDI + VHC NEB

USAL 0.5 (µg) 14.7 (7.2) 14.1 (7.6)

USAL 0.5 (% nominal) 2.94 (1.45) 0.28 (0.15)*

USAL 24 (µg) 194.0 (53.4) 251.8 (55.1)*

SAL left i the device (µg) 231.3 (47.6) 3117(414)*

SAL dose emitted (µg) 268.7 (47.6) 1883(413.5)*

USAL 0.5 (% dose emitted) 5.74(2.99) 0.79 (0.51)*

FEV1 pre (% predicted) 42.2 (15.6) 46.9 (18.2)

Δ FEV1 in 60 min 9.6 (12.4) 6.5 (7.7)

Nebulizers VS Inhalers: And the Winner Is?

LC Plus+Turboboy

LC Star+Turboboy

LC Star+air

Sidestream+Portaneb

Cirrus+Novair II

Ventstream+Portaneb

Ventstream+air

Bary 1999

Nominal dose 5 mg Salbutamol P

edia

tric

bre

ath

ing

Sim

ula

tor

Inhaled drug %

Drug lost to ambient %

Drug lost in nebulizer %

Time min

Misty-Neb 17.2+0.4 26.8+0.7 52.3+0.6 11.9+3.0

SideStream 15.8+2.8 17.3+0.4 63.4+3.0 9.5+0.1

Pari LCD 15.2+4.2 18.3+0.8 62.5+4.0 8.4+1.2

Circulaire 8.7+1.0 12.3+0.8 75.8+0.5 7.0+0.5

AeroEclipse 38.7+1.3 6.6+3.3 51.0+2.1 14.4+1.1

2.5 mg in 3 ml of albuterol sulfate and powred by O2 at 8L/min

Rau 2004

INITIAL TREATMENT OF ACUTE ASTHMA IN CHILDREN >2 YRS

β2 agonists should be given as first line treatment. Increase β2 agonist dose

by two puffs every two minutes according to response up to ten puffs.

Children with acute asthma at home and symptoms not controlled by up to 10

puffs of salbutamol via pMDI and spacer, or 2.5-5 mg of nebulised salbutamol,

should seek urgent medical attention. Additional doses of bronchodilator

should be given as needed whilst awaiting medical attention if symptoms are

severe.

Paramedics attending to children with acute asthma should administer nebulised

salbutamol driven by oxygen if symptoms are severe whilst transferring the child

to the emergency department.

Children with severe or life threatening asthma should be transferred to hospital

urgently.

There is good evidence supporting recommendations for the initial treatment of acute

asthma presenting to primary and secondary healthcare resources. There is less

evidence to guide the use of second line therapies to treat the small number of severe

cases poorly responsive to first line measures.

British Guideline 2012

INHALED β2 agonists

2-4 puffs of a salbutamol 100 ug repeated every 10-20 minutes according to clinical

response might be sufficient for mild attacks although up to 10 puffs might be

needed for more severe asthma.

Single puffs should be given one at a time and inhaled separately with five tidal

breaths. If hourly doses of bronchodilators are needed for more than 4-6 hours, the

patient should be switched to nebulised bronchodilators.

Children with severe or life threatening asthma (SpO2 <92%) should receive

frequent doses of nebulised bronchodilators driven by oxygen (2.5-5 mg salbutamol

or 5-10 mg terbutaline).

Doses can be repeated every 20-30 min. Continuous nebulised β2 agonists are of

no greater benefit than the use of frequent intermittent doses in the same total

hourly dosage. If there is poor response to the initial dose of β2 agonists,

subsequent doses should be given in combination with nebulised ipratropium

bromide.

British Guideline 2012

TREATMENT OF ACUTE ASTHMA: SABA

A SABA is recommended for all patients

The repetitive or continuous administration of SABAs is the most effective means of reversing airflow obstruction. Continuous administration of SABA may be more effective in severely obstructed patients. Because of the risk of cardiotoxicity, use only selective SABA (albuterol, levabuterol) in high doses. In mild or moderate exacerbation, equivalent bronchodilation can be achieved either by high doses (4-12 puffs) of SABA by MDI + chamber under supervision of trained personnel or by nebulizer therapy. Nebulized therapy may be preferred for patients who are unable to cooperate. The onset of action of SABAs is less than 5 minutes; repetitive administration produces incremental bronchodilation. Duration of action of brochodilation from SABAs in severe asthma exacerbation is not known (can be significantly shorter than that in stable asthma)

NHLBI-NAEPP 2007

BRITISH GL

MDI via spacer Salbutamol or

Terbutaline

10 puffs given singly at 30-60 second

intervals (repeat after15-30 minutes if necessary)

Nebulised

(Repeat after 15-30

minutes if necessary)

salbutamol > 5 yrs: 5 mg

< 5 yrs: 2.5 mg

Terbutaline > 5 yrs: 10 mg

< 5 yrs: 5 mg

Recommended dosages of inhaled β2 agonists

LG SIP 2008

Nebulizzazione 0,15 mg/Kg/dose (1 goccia 0,25 mg), (10 Kg …. 6 gocce)

ripetere ogni 20-30 minuti (max 5 mg) (33Kg.....20 gocce)

Spary predosato

2-4 (200-400 mcg) spruzzi, fino a 10 spruzzi nelle forme più

gravi, ripetuti se necessario ogni 20-30 min nella prima ora,

poi ogni 1-4 ore secondo la necessità.

Nebulizzazione

continua 0,5-5 mg/kg/ora

Kantar 2015