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?"
SPACER SYSTEMS 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. Medihaler pmdi: The original pmdi was equipped with an elongated mouthpiece, arguably making it the first tube spacer. Maison 1956
Charles Thiel
SPACER SYSTEMS I soon tired of gluing my fingers together and the following year a plastics company manufactured the device Beclomethasone Aerosol by Reservoir Bottle (BARB). Spacer system comprised a 1.2-L vinegar bottle and facemask with one-way valve. Freigang 1977
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 Electrostatic attraction time dependent + - + - + - + Dead space Leaking Leaking Valve insufficiency Sedimentation time dependent
Mean net fine-particle-dose electrical charge of aerosols from commercially available metered-dose inhalers
Barry 1999
Rau 2006
ELECTROSTATIC CHARGE new detergent-coated Kwok 2006
ELECTROSTATIC CHARGE Dose delivered to filter during 100 consecutive acutations of BUD- Nebuchamber (nonelectrostatic) and FP-Babyhaler (electrostatic) Nebuchamber Babyhaler Increase 0.8% in day Berg 1998
dead space Shah 2006
TV 18 mon TV 6 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
Obligate nasal breathing in the newborn 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.
GROWTH OF NASAL-LARYNGEAL AIRWAYS IN CHILDREN Xi 2013
GROWTH OF NASAL-LARYNGEAL AIRWAYS IN CHILDREN Inhalation airflow under quiet breathing conditions Xi 2013
PULMONARY OBSTRUCTION Lung volumes and ventilation distribution in healthy and obstructive disease. Tidal Volume, Total Lung Capacity Functional Residual Capacity Lannefores 2006
INHALATION 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.
Adults Normal (n=10) FEV1 110 % FEF25-75 103% Mean dose SAL mg 3.28 (2.86 3.88) Lower plasma concentration 1.31 vs 2,4 and 2.45 ng/ml 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
EFFECT OF ph ON ALBUTEROL TRASPORT 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. Unwalla 2012
SALBUTAMOL 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 Starkey 2014
SALBUTAMOL IN AIRWAY OBSTRUCTION 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. Starkey 2014
SALBUTAMOL 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. Starkey 2014
BIGGER MAY BE BETTER: TARGETED Β2-AGONIST THERAPY? Placebo Δ 15 µg of 6µm pmdi 200µg 15 µg of 3 µm 15 µg of 1.5µm 30µg of 6µm pmdi 200µg 30µg of 3 µm 30µg of 1.5µm Placebo Usmani 2005
SALBUTAMOL SYSTEMIC EFFECTS Glucose (rapid dose related) & insulin (inadequate) BSL liver muscle ß 2 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 ß 1, direct inotrope, prolongs QT c interval, cardiac ß 2 exacerbated by low K + low Mg increases minute ventilation metabolic rate oxygen consumption CO 2 production Imbalance fast- and slow-twitch muscle groups of extremities Tremor development of tolerance (reduced ß receptor sensitivity) Sears 2002 Tobin 2005
SIDE EFFECTS SALBUTAMOL 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) Rohr 1986
Tremor,Hypo-K - Direct stimulation skeletal muscle β 2 -adrenoceptors Tachicardia - Direct stimulation cardiac β 2 - adrenoceptors - Indirect activation periphral R (vasodilatation) and consequent reflex vagal withdrawal Fowler 2001
SIDE EFFECTS SALBUTAMOL p = 0.373 (p < 0.001) 26 patients; age >16 years Nebulized salbutamol (2.5 mg) x3 times at every hour. Sahan 2012
SALBUTAMOL KINTEICS INTRAVENOUS ADMINISTRATION 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 ( ) Starkey 2014
INTRAVENOUS SALBUTAMOL DOSING RECOMMENDATIONS BRITISH NATIONAL FORMULARIES FOR CHILDREN AND ADULTS 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 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
L/min SABUTAMOL: NEBULIZED VS I.V. mm Hg Neb superior in hypercapnic acute asthma 200 PEF ** Pa CO2 Clinical Index 15 150 50 10 * 100 * 50 40 5 ** ** N = 47 0 1 hr 0 1 hr 0 NEB Group IV Group salbutamol NEB : 5mg x 2 IV : 0.5mg in 1h *p 0.05 **p 0.001 1 hr Salmeron 1994
ASTHMATICS: TOO DRUNK Time response curve for breath alcohol level using Ethylometer (679T) after Salamol, inhalation for 16 normal volunteers O Conell 2006
Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma 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 Updated January 2008 Cates 2008
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 Forest plot of comparison 1 Spacer (chamber) versus Nebuliser (Multiple treatment studies) outcome: 1.1 Hospital admission Cates 2008
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: 1.3 Duration in emergency department (hours) 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 Forest plot of comparison 1 Spacer (chamber) versus Nebuliser (Multiple treatment studies) outcome: 1.9 Rise in pulse rate (% baseline). Cates 2008
19 asthmatics (12 ) mean (SD) age 53.7 (17.1) 2-4 days after exacerbation SAL urine 30, SAL urine 24 (HPLC); lung function 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) Mazhar 2006
Nebulizers VS Inhalers: And the Winner Is? 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) Mazhar 2006
Pediatric breathing Simulator Nominal dose 5 mg Salbutamol LC Star+Turboboy LC Plus+Turboboy LC Star+air Sidestream+Portaneb Ventstream+air Ventstream+Portaneb Cirrus+Novair II Bary 1999
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 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. 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. 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
Recommended dosages of inhaled β2 agonists 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 Terbutaline > 5 yrs: 5 mg < 5 yrs: 2.5 mg > 5 yrs: 10 mg < 5 yrs: 5 mg LG SIP 2008 Nebulizzazione Spary predosato Nebulizzazione continua 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) 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. 0,5-5 mg/kg/ora
Kantar 2015