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