Effective Aerosol Delivery in Acute Care

Effective Aerosol Delivery in Acute Care Jim Fink, RRT, PhD, FAARC, FCCP Chief Science Officer, Aerogen Pharma Corp., San Mateo, CA USA Visiting Professor, Dept of Physical therapy, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil Adjunct Faculty, Rush, Chicago CSRC, 50 th Annual Convention Monterey

Medications via Aerosol to Acutely Ill Patients u Bronchodilators u Anti-infectives u Prostanoids u Anticoagulants - Heparin u Diuretics u Insulin u Mucokinetics u NOTE: Mucomyst (N-Acetylcystein) no evidence of benefit by aerosol on or off the ventilator

Intermittent Positive Pressure Breathing (IPPB) 30% Less Aerosol to lung than Neb Alone

Macintyre Crit Cre Med 1985

Fuller et al. 1990. ARRD 141:440-444.

Clinical response to pmdi during CMV u Dose response in mechanically ventilated patients with COPD. u MDI-spacer & albuterol Dhand R AJRCCM 154;388:1996 u Similar decline in airway resistance with 4, 8 and 16 puffs of albuterol.

Toxicity uincrease in heart rate after 28 puffs of MDI albuterol. AJRCCM 1996;154:388 uventricular ectopy and SVT developed after 3-6 times normal nebulizer dose. Am Rev Resp Dis 1993;148

Comparison of Serum Albuterol Levels: Normal Controls and Intubated/Ventilated Subjects Duarte et al. 1996, AJRCCM

From ventilator Medication mist To patient Baffles Medication cup Sterile buffer water Fountain, generated by ultrasonic waves Cable from control unit Ultrasonic waves Ultrasonic generator (not visible) Maquet SUN 145 Ultrasonic Nebulizer with power control module.

Neb Position Pos 1 - Between ETT & Y Pos 2-6 in from Y Pos 3-6 in from Vent Ventilator Circuit Heated Unheated Heated Unheated Heated Unheated JN 4.66 (0.5) 7.62 (0.9) 3.61 (0.2) 9.66 (1.5) 5.98 (0.1) 14.66 (1.5) VM 12.82 (0.5) 14.54 (1.0) 16.79 (2.6) 30.24 (1.0) 8.39 (2.1) 24.20 (1.2) UN 10.07 (3.9) 10.70 (1.5) 16.53 (4.3) 24.68 (4.4) 4.59 (2.0) 10.51 (0.3) pmdi 7.6 (1.3) 22.1 (1.5) 17 (1.0) 27.8 (3.3) 2.5 (0.8) 7.9 (1.5) Ari et al, Respir Care 2010

Ari et al, Respir Care 2017

Aerosol Delivery During PSV and VCV Dugernier Ann Critical Care 2016

Position 1 Position 2 ADULT STUDY PEDIATRIC STUDY Mode Volume Control Volume Control Tidal Volume 500 ml 100 ml Respiratory Rate 20/min 20/min PEEP 5 cmh 2 O 5 cmh 2 0 Waveform Descending Descending Bias Flow 2 and 5 lpm 2 and 5 lpm Ari et al. Respiratory Care 2010; 55 (7): 845-851.

30 25 With Bias Flow VM and JN more Efficient Placed Prior to Humidifier Adult % Inhaled Dose 20 15 10 5 0 16 Bias flow 2 Bias flow 5 Bias flow 2 Bias flow 5 Position 1: At the "Y" Position 2: Prior to Humidifier JN VM As Bias flow Increases deposition decreases Peds % Inhaled Dose 14 12 10 8 6 4 JN VM VM > JN 2 0 Bias flow 2 Bias flow 5 Bias flow 2 Bias flow 5 Position 1: At the "Y" Position 2: Prior to Humidifier Ari et al. Respiratory Care 2010; 55 (7): 845-851.

Bench study: Nebulizer position determines nebulizer performance Albuterol Loading volume 2.5mg/ 3ml Nebulizer Hudson Updraft II Opti-Neb At Ventilator Nebulizer position At Humidifier At Y-piece 30cm Before Y- piece 5.4 0.6 4.7 0.8 2.0 0.1 4.3 0.8 Salter 8900 3.1 0.9 4.6 0.9 2.8 0.4 2.9 0.7 Maquet Ultrasonic 12.8 1.5 17.1 1.5 8.7 0.7 10.5 2 Aeroneb Solo 28.5 8.6 33.3 3.6 8.7 2.5 10.3 3.3 u Bias Flow 2L/min The Vibrating Mesh Nebulizer performance was 5-6 times superior to small volume nebulizers locations. Berlinski & Willis, 2013.

Hui-Qing Ge 2018 Aerosol Delivery with APRV

Aerosol Delivery with APRV µg of albuterol (mean SD) and percentage of nominal dose Position 1 Position 2 Position 3 Insp limb at Y Humidifier outlet Humidifier inlet PCV 796.9 13.9 971.9 69.4 1490.6 61.1 (15.9%) (19.4%) (29.8%) a PCV BF6 1046.88 27.1 1057.3 52.9 1182.3 61.4 (20.8%) b (21.1%) (23.6%) ab APRV 475.0 28.4 893.8 40.4 1153.1 99.7 (9.5%) (17.9%) (23.1%) ab APRVs 1153.1 13.1 d 1368.8 37.6 1706.2 60.9 (23.1%) (27.4%) (34.1%) ac Hui-Qing Ge 2018

VMN with Adapter vs Jet Neb Alcofocado ATS2016

Mouthpiece Aerosol Delivery 6 Healthy Adults Vibrating Mesh with adapter vs Jet Neb A B Vibrating Mesh Jet neb P value 34.1 ± 6 5.2 ± 1.1 <0.001 Lung deposition was six times greater with Vibrating Mesh (Aerogen Ultra) vs the Jet Neb 23 11. Dugernier et al.

COPD Clinical Outcome Data Beaumont Hospital COPD Study (VM vs JN) u VM (Aerogen Ultra) group achieved a significantly greater improvement in post-bronchodilator FVC compared to the Jet Neb group u Only the VM group demonstrated significant reductions in postbronchodilator BORG breathlessness score. 24 22. Cushen, V., et al.

VMN with Adapter vs Jet Neb in the Emergency Department Dunne AARC 2016

Aerosol Deposition During Neonatal Mechanical Ventilation u10 ventilated infants/ 13 nonintubated umdi/spacer 200 ug Neb 100 ug over 5 min uventilated infants 0.98% MDI 0.98 0.19% NEB 0.22 0.08% u Nonventilated infants 0.67% MDI 0.67 0.17% NEB 0.28 0.014% 1996 Fok et al. Ped Pulmonol 1996 21:301-9

Figure 9 Measurements of respiratory system resistance (Rrs) before, and at 15, 30, 60 and 120 min after salbutamol treatment via the metered dose inhaler (MDI), the jet nebulizer (Jet: Sidestream) and the ultrasonic nebulizer (US). * post treatment values were signficiantly lower than the pretreatment Rrs, p<0.0001. Fok et al. Eur Respir J1998;12(1):159 164.

Vibrating Mesh - Drug Deposition in animal model of infant ventilation MistyNeb Aeroneb Pro Aeroneb Pro MistyNeb Deposition in the lung 12.6% 0.5% (p=0.006) ~25-fold greater lung deposition with Aeroneb Pro compared to a Jet nebulizer during infant ventilation Dubus et al. 2005 Aerosol deposition in neonatal ventilation

Laboratory Assessment Of Aerosol Delivery During Infant ncpap Ventilation impact of nebulizer position and breath actuation on drug delivery to collection filter during test lung ventilation Gas Source (10 LPM) VMN breath simulator (0.5 LPM) nasal prongs collection filter bubble cpap (PEEP 10 cm H 2 O) Standard Model of Infant Respiration on ncpap VMN is positioned in main gas path; test lung is sampling from this gas flow at 60 BPM with 8 ml tidal volume and 1:2 I/ER (only 5% of total) Inhaled Mass of albuterol measured on collection filter 1.3% Gas Source (10 LPM) breath simulator (0.5 LPM) Move Position Of VMN move position of aerosol generator between gas flow and patient airway; ventilation settings unchanged Inhaled Mass of albuterol measured on collection filter 22-26% Gas Source (10 LPM) breath simulator (0.5 LPM) controller SYNCH sensor Breath Actuate VMN a sensor coordinates actuation of the aerosol generator with patient s inspiratory maneuver Inhaled Mass of albuterol measured on collection filter 38-45% VMN: Vibrating Mesh Nebulizer (Aerogen Pro) LPM: Litres Per Minute BPM: Breaths Per Minute I/ER: Ratio of Inspiratory to Expiratory Time PEEP: Peak End Expiratory Pre

Challenges In Surfactant Delivery May impact triggering, PEEP, Tidal Volume inefficiency of gas powered nebulizers drug loss due to continuous nebulization during respiratory cycle nebulizers may become clogged and inoperable, or degradation of aerosol limitations inability to sufficiently provide drug prior to onset of inhalation may create deadspace low drug deposition in infants (<3%) frequently require 3-4 x dose used with direct instillation

Nasal Delivery with Breath Synchronization 3 x Greater Lung Dose

Breath Synchronized Aerosol Delivery of Surfactant via Endotracheal Tube During Mechanical Ventilation

Oxygen Index Instilled vs Aerosol Dose 14 12 10 Oxygenation index 8 6 4 2 0 Pre Lavage Post Lavage 0.5 hr Post Surfactant 1.0 hr Post Surfactant 1.5 hr Post Surfactant 2.0 hr Post Surfactant 2.5 hr Post Surfactant 3.0 hr Post Surfactant Direct Instillation Surfactant 108 mg (catheter) Aerosolized Surfactant 108 mg (Vibrating Mesh Nebulizer ) Aerosolized Surfactant 54 mg (Vibrating Mesh Nebulizer ) Control (No Surfactant)

Ventilation Efficiency Index 0.3 0.25 Direct Instillation Surfactant 108 mg (catheter) Aerosolized Surfactant 108 mg (Vibrating Mesh Nebulizer ) Control (No Surfactant) Ventilation Efficiency Index 0.2 0.15 0.1 0.05 * * n=2 0 Pre Lavage Post Lavage 0.5 hr Post Surfactant 1.0 hr Post Surfactant 1.5 hr Post Surfactant 2.0 hr Post Surfactant 2.5 hr Post Surfactant 3.0 hr Post Surfactant VEI [3800/PIP*rate*PaCO 2 ], *P<0.05 between Aerosolized and Instilled Surfactant

Complications: Acute Effects Total # Events 7 6 5 4 3 2 1 * * * 0 Bradycardia Hypotension High PIP Direct Instillation (catheter) Aerosolization (vibrating mesh) AARC Guideline of surfactant administration (Hazards/Complications) Plugging of ET Tube by surfactant: Increased PIP Flow Sensor accuracy (in VG Mode): Increase or Decrease PIP Increased need for Oxygen: SpO2 Bradycardia due to hypoxia Tachycardia due to agitation, with reflux of surfactant in ETT Deterioration Criteria Guidelines (compared with baseline) INCREASE PIP 5 HR 20% BP 20% DECREASE PIP 5 HR 20% BP 20% SPO2 90% * Indicates no deterioration for aerosolized surfactant No acute reductions in PIP, SpO2, or hypertension noted with either delivery method

Sunbul FS, Pediatric Pulmonology 2014

HFNC Animal Model Of Human Infant nebulization by nasal cannula with VMN at 3 gas flow rates; aerosol deposition decreases with increased gas flow 8 4 2 L/min airflow through NHF circuit delivery of Tc 99m -DTPA labeled saline to macaque monkeys using Aerogen Solo & Fisher+Paykel Optiflow Reminiac F. et al, Pediatric Pulmonology, 2016

Adult HFNC (In Vitro) u In this bench model, aerosol delivery increased with respiratory distress compared to quiet breathing 14 12 * 30L/min 45L/min 60L/min RESPIRABLE MASS (%) 10 8 6 4 2 * p<0.01 overall comparison, p<0.01 between breathing patterns 0 Quiet Breathing Respiratory Distress VM deposited significantly more drug in the lungs at the lower flow rate of 30 l/min than 45 l/min and 60 l/min. Adult model of respiratory distress (insp flow 55 L/min) compared to quiet breathing (15 l/min) VM demonstrated more aerosol particles with diameters of 0.4 4.4 µm, no added gas flow and a shorter nebulization duration compare to JN 38 17. Réminiac et al. J Aerosol Med Pulm Drug Deliv

Inhaled Mass (n=5) Distressed Respiratory Pattern % Inhaled Dose (n=5) Inhaled Mass (n=5) % Inhaled Dose (n=5) Inhaled Mass (n=5) % Inhaled Dose (n=5) P value Gas/ Flow 10 L/min 10 L/min 30 L/min 30 L/min 50 L/min 50 L/min Oxygen 100% Heliox (80/20) Inhaled Mass (mg) (n=3) % Inhaled Dose (n=3) Inhaled Mass (mg) (n=3) % Inhaled Dose (n=3) Inhaled Mass (mg) (n=3) % Inhaled Dose (n=3) Gas/ Flow 10 L/min 10 L/min 30 L/min 30 L/min 50 L/min 50 L/min Oxygen 100% Heliox (80/20) Dailey, Fink 2017.652±.16 13.2±3.6 1.644±.24 32.8±5.0 1.263±.08 25.4± 1.8 <.01*.873±.15 17.4±3.1 1.757±.24 35.2± 4.7 1.501±.20 29.8±4.1 <.01* Resting Respiratory Pattern P value.667±.032 26.7±1.29.289±.029 11.6±1.17.088±.004 3.5±0.17 <.01*.684±.059 27.4±2.37.356±.022 14.2±0.89.147±.43 5.88±1.73 <.01*

Nielson, DiBlasi Resp Care 2017

Nielson, DiBlasi Resp Care 2017

Nielson, DiBlasi Resp Care 2017

HFNC Adult Imaging 23 healthy adults received aerosol therapy with vibrating mesh (VM) during HFNC (normal tidal breathing) 10L/min 30L/min 50L/min Heated 11.8 4.9 3.76 1.36* 2.23 0.81* *p<0.05 compared to 10L/min o Alcoforado et al. ISAM poster presentation 2016 Inverse relationship of lung deposition to flow rates 18. Alcoforado et al. ATS 2016 44

Aerosol Delivery Non Invasive Ventilation Place neb between leak and patient Drug delivery influenced by: Nebulizer position Breathing frequency IPAP/EPAP settings Chatmongkolchart S et al Crit Care Med 2002;30:2515-2519.

Position Neb Between Leak and Mask for best delivery Nebulizer Position closer to filter (A) Inhalation Filter (µg) Nebulize r (µg) Position farther from filter (B) Inhalation Filter (µg) Nebulize r (µg) Aeroneb 2573 151 891 163 936 273 1001 263 Sidestrea m 1207 161 2261 795 341 70 2420 154 Abdelrahim ME et al J Pharmac Pharmacol 2010; 62;966-72.

u Bench Study: Pediatric aerosol delivery during non-invasive ventilation with the NIVO Comparison of aerosol delivery with the NIVO and the Aeroneb Solo during non-invasive ventilation White Resp Care 2013

Pediatric Non Invasive Vent with 2 Limb Circuit Velasco, Berlinski Resp Care 2017

Vibrating Mesh (VMN) > 2 fold more than Jet VMN and pmdi similar dose efficiency

Lung Dose JN vs Mesh Lung deposition (corrected for absorption) with the Mesh was > 3 fold greater than JN, independent of dose volume used with the MESH. Neb/Dose JET NEB 3 ml MESH 3 ml Total Lungs 1.97 ± 0.8% 8.26 ± 1.1 %* Inhaled Dose 7.31 ± 4.3% 27.3 ± 10.1 %* *p<0.0001 (MESH 3 ml vs JN 3 ml) and **p<0.007 (MESH 1 ml vs JN 3 ml).

NIV VMN vs JN COPD Patients Galindo-Filho In press

Pulmonary Drug Delivery System Amikacin Inhale

Delivery of inhaled amikacin during mechanical ventilation targets the lung without systemic toxicity 4000 Concentration (µg/ml) 3000 2000 1000 300 250 200 150 100 50 Target lung concentration to treat resistant bacteria Blood Lung Toxic blood level of amikacin IV amikacin, Dose = 500mg BID NKTR-061, Dose = 400mg BID

Colistin by Aerosol + IV vs IV Alone Boisson ACC 2014

Conclusion u Many inhaled drugs were approved based on studies in spontaneous breathing subjects with lung doses of 10 20%. u Lung dose with standard JN can deliver as little as 3% of dose to the lung. u Many of the devices used in Neonates, infants, children and adults can achieve >10% lung dose with conventional ventilation, NIV and HFNC. u Choice of aerosol generator and placement makes a difference in drug delivery to the lung u Selection of Drug Dose for Specific Device can Achieve Effective Lung Doses jfink@aerogenpharma.com