Aerosolized Surfactant: where we are at?

Anna Lavizzari, MD

NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Department of Clinical Sciences and Community Health,

University of Milan, Italy

NICU Mangiagalli, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan

Disclosures

I have been a consultant for Chiesi S.p.A and Getinge.

I have received travel grants from Vapotherm S.p.A and Fischer&Pykel.

Endotracheal surfactant: PROs?

Exogenous surfactant reduces:

↓ Risk and severity of RDS

↓ Risk of air-leak

↓ Mortality

↓ Death or BPD

Soll R, Özek E. Cochrane Database of Systematic Reviews, 1997

Endotracheal surfactant & INSURE: CONs?

Bleeding, trauma, perforation of the airways and esophagus

Painful procedure!!

Haemodynamic instability, bradicardia,

changes in ABP and CBF

Selective right main bronchus intubation

Lung injury associated to PPV

Economic cost

Routes for Surfactant Administration

ENDOTRACHEAL

INSURE

LISA/MIST LMA

PHARYNGEAL INSTILLATION

NEBULIZATION

“Less-Invasive” Surfactant Administration

ENDOTRACHEAL

INSURE

LISA/MIST LMA

PHARYNGEAL INSTILLATION

NEBULIZATION

“Less-Invasive” Surfactant Administration

ENDOTRACHEAL

INSURE

LISA/MIST LMA

PHARYNGEAL INSTILLATION

NEBULIZATION The least invasive!

Advantages of Nebulization

Drug delivery directly to the

target site

↓ doses required for the

therapeutic effect

Faster onset of action

Reduced systemic bioavailability

Reduced systemic side effects

Hess. Resp Care 1995, Roche N, Huchon GJ J Aerosol Med 2000

Efficacy of Nebulization

LUNG DEPOSITION

1. DRUG

2. PARTICLE

SIZE

3. PATIENT

4. DEVICE

Cole CH, Resp Care 2000

Mass Median Aerodynamic Diameter (MMDA), Speed & Lung Deposition

Particles’ speed affect deposition: high speed promotes inertial impaction

0.8 to 2 um optimal for alveolar deposition

Patients Factors

Small-calibre upper and lower

airways

Prone to obstruction

Small tidal volumes

Associated with low inspiratory

flow

Rapid and irregular respiratory rate

Shorter time for delivery

The ideal nebulizer should…

1. Deliver an adequate amount of drug into the lung

2. Minimise oral/pharyngeal deposition

3. Be easy to apply

4. Meet patient’s need

5. Be acceptable in term of cost-benefits

Nebulizers

Jet-nebulizer

Ultrasonic

Vibrating Mesh

Low cost

Large proportion of the administered dose is retained either as residual volume within

the device, absorbed onto the baffles or is expired poor efficiency of surfactant

nebulization.

Nebulizers

Jet-nebulizer

Ultrasonic

Vibrating Mesh

Large quantities of small-

diameter particles (0.8–3.1 m) and achieve more efficient aerosol deposition than jet

nebulizers.

Faster than jet!

The acoustic waves may denaturate protein and loss phospholipids. More expensive.

Nebulizers

Jet-nebulizer

Ultrasonic

Vibrating Mesh Vibrating mesh can

be customized. More efficient drug

delivery.

Single-use. More expensive.

Issues in Surfactant Nebulization

1. Which device should we use?

2. How much surfactant is delivered into the alveoli? What is the optimal dose?

3. Is it safe?

4. Which is the target population?

5. Is it doable at bed-side? How long does it take? Interfaces? Respiratory supports? Do they count?

6. Is it convenient from a cost-benefits prospect?

Surfactant Nebulisation

• Pilot study

• aerosol of 𝛃- 𝛄-dipalmitoyl- L -α –lecithin

• into the incubator of 11 spontaneously breathing infants with RDS for 30 min and in one case up to 4 h

clinical effect in 8 of the 11 patients treated assessed by retraction score.

Robillard E, Alarie Y et al. Canad. Med. Ass. J Jan 11 1964

• Aerosolization of surfactant (survanta 110

ml/kg) in tracheostomized and ventilated

130-132-day gestation preterm lambs

with RDS.

• continuously nebulized via the

tracheostomy from 30 min of life, for 3 h

• using a jet nebulizer

• Nebulized surfactant-treated animals

had improved compliance, ventilation efficiency index and oxygenation

compared with saline.

• Most of the surfactant was trapped in the filter, and the T piece and expiratory tubing!!

• only 1.9–2.7% deposited in the lung

How can such a small dose be clinically

beneficial?

Evidence from animal studies – intubated

Nebulized surfactant produces a more (or equally) homogeneous lung distribution in intubated animal compared to bolus instillation

Dijk – rabbits [Intensive care Med, 1997]

Schermuly [AJRCCM, 2000]

Saline lavaged isolated perfused rabbit lungs

Ultrasonic nebulisation vs bolus instilled

Lung deposition 8.8 mg/kg

Wagner [Crit Care Med 2000]

Similar regional distribution, however less variable in the nebulized group

Evidence from animal studies – nCPAP

Wolfson, Ped Res 2011 • 130-132-day preterm lambs

• Randomized to CPAP alone or CPAP plus aerosolized surfactant

• Increased compliance, increased tidal volume and reduced inflammatory markers (IL-6, IL-8 and myeloperoxidase) following aerosolized surfactant

• Vibrating MesH nebulizer

Nebulised Surfactant and extra-pulmonary effects: is it Safe?

14 preterm lambs (85% gestation)

randomly assigned to:

SF-aero

ET SF-bolus

Nebulization over a period of 20 min delivered

intratracheally by means of inhalation catheters

connected to a pneumatic compressor

Vent. Efficiency Index

OI

2013 Surf- BOLUS

Surf- AERO

Surf- BOLUS Surf- AERO Heart Rate Mean Arterial Blood Pressure

Carotid Blood Flow pCO2

Rey-Sanatana et al. Ped Res 2013

Total Lung Injury Score

Rey-Sanatana et al. Ped Res 2013

Clinical Trials of Nebulized Surfactant

SURFACTANT METHOD POPULATION OUTCOME

Jorch G 1997 Alveofact Jet nebuliser 28-35 weeks (n =

20)

A-aO2 gradient, pCo2 and

Silverman score improved

Arroe M 1998 Exosurf Side stream

nebuliser

23-36 weeks (n =

22)

No significant benefit

Berggen E 2000 Curosurf Jet nebuliser

Infant flow +

CPAP

27-34 weeks (n =

34)

No significant benefit

Finer N 2010 Aerosolised KL4 Aeroneb (mesh)

+ CPAP

28-32 weeks (n =

17)

Safe

Abdel-Latif ME, Osborn DA, 2012

Jorch, 1997 (n=20)

• Group characteristics

• 31 (28-35) w

• 1.7 (1.2-2.5) kg

• 5 (2-9) h

• Design

• Uncontrolled multicenter study

• Jet nebuliser 8L/min via T connector to NP tube with pharyngeal bubble CPAP for 20-50 min total

• MMDA < 4 µm

• 150 mg x 2 , total 300 mg/kg Alveofact®(Thomae GmbH Germany)

• Initial FiO2 0.41 (0.21-0.75)

• Initial A-aO2 181 (46-427) mmHg

• Results:

• Immediate ↓(A-aO2) and ↓ pCO2

• Most improvements after 150 mg/kg surfactant

• Increased secretions notes as side effect

• 6/20 required intubation

Arroe, 1998 (n= 22)

• Results:

• No adverse effects, but no improvement in clinical variables or a/A-ratio

• 8 patients required IMV within 2 h of last treatment

• Group characteristics

• 23–36 weeks

• <3 days

• Design

• Uncontrolled

• Synthetic surfactant

(Exosurf ) 108, 216 or

432mg DPPC

• 2 x 30 min treatment, 6 h

apart

• Side Stream 45 nebulizer in-

line with CPAP circuit

• above ‘Y’ connector

• MMAD unknown

Berggren, 2000 (n= 34)

• Group characteristics • 27–34 weeks

• <2 days

• Design • CPAP vs. CPAP+neb Curosurf 480 mg (34 ml)over 3 h

• CPAP 3–5 cm H2O

• Jet nebulizer (Ajolos, Sweden) with aerosol at CPAP adaptor, 7 l/min

• MMAD <2 m

• Results: • No change in days mechanical ventilation or duration of CPAP

• No change in oxygenation (a/A ratio or duration supplemental O2)

• No difference in CLD, PDA, airleak

Finer, 2010 (n=17)

• Background:

• Prophylactic aerosolization of surfactant delivered via nCPAP

• Group characteristics

• 30 (28-32) w

• 1.5 (1.0-2.3) kg

• <0.5 h!

• Design

• Uncontrolled pilot feasibility/safety study

• Vibrating membrane nebulizer (Aeroneb Pro)

• Nebulizer output 0.24 mL/min

• 20mg/mL AerosurfTM x 3 h

• Volume per treatment = 15-54 ml

• Maximum 72 mg of total phospholipids

• Up to 3 treatment in 48 hours permitted

• @ 3 h interval (group 1, n= 11)

• @ 1 h interval (group 2, n=6)

• Results

• Transient ↓SpO2 in 9/17 infants not associated with ↓HR or ABP

• ↓FiO2 within 6 h

• 70% required only one treatment

• 30% required ET surfactant

• 24% diagnosed RDS at 24 h

Novelties!!

Clinical trials on Nebulized Surfactant

• Only a few studies in human infants published - small ( max 35

subjects)

• Designed as uncontrolled pilot studies (except Berggren et al)

• The main side effects: increased secretions with apnea and

transient mild hypoxia

• Jet poor efficiency

• Overall, the treatments appear to be safe and reasonably well

tolerated

• In Finer et al: aerosolized surfactant administered relatively

early evidence of clinical benefit

Clinical Trials of Nebulized Surfactant

SURFACTANT METHOD POPULATION OUTCOME

Jorch G 1997 Alveofact Jet nebuliser 28-35 weeks (n =

20)

A-aO2 gradient, pCo2 and

Silverman score improved

Arroe M 1998 Exosurf Side stream

nebuliser

23-36 weeks (n =

22)

No significant benefit

Berggen E 2000 Curosurf Jet nebuliser

Infant flow +

CPAP

27-34 weeks (n =

34)

No significant benefit

Finer N 2010 Aerosolised KL4 Aeroneb (mesh)

+ CPAP

28-32 weeks (n =

17)

Safe

Pillow J

CureNeb study Curosurf Pari eFlow

(Mesh) + CPAP

via nasal mask

29-33 weeks (n=

70)

Reduction in CPAP failure

in 32-33 weekers

Vibrating Membrane Nebuliser (MesH)

• Aerosol droplets are generated by a perforated

vibrating mesh

• Customizable to the physicochemical properties of

a particular drug formulation by altering:

- size, number and distribution of the holes,

- power and frequency to the piezo element

• Highly uniform particle size

• Generate low flow that minimize aerosol dilution

• Minimal residual drug deposition

Vibrating Membrane Nebuliser (MesH)

• As only low shear stresses are exerted on the fluid,

aerosolization of fragile molecules such as proteins or genes

are possible without denaturation

• Markedly increase the proportion of aerosolized drug

delivered to the patient and lung delivery efficiencies

• Highly portable (battery or alternating current) (nb delivery

room option)

• Not dependent on a gas flow

• Membrane pores may clogg, in partic with the viscosity and

protein content of the solution careful attention to

cleaning/single-use or require regular replacement.

• More expensive than jet nebulizer units.

• Cost-efficient and clinically effective.

• Objective: To evaluate if nebulised surfactant reduces intubation requirement in

preterm infants with respiratory distress treated with nasal continuous positive

airway pressure (nCPAP).

• Double blind, parallel, stratified, randomised control trial, pilot Study

• Primary outcome: need for intubation and duration of MV in the first 72h

• A customized, Pari eFlow vibrating membrane nebulizer; Curosurf 200 mg/kg 1st

dose, 100 mg/kg 2nd dose, after 12 hours for persistent supplemental oxygen

requirement + bubble CPAP & heated dry circuit

Arch Dis Child Fetal Neonatal, July 2018

GA 29+0–33+6 weeks,

<4 hours’ of age, and clinical

signs suggestive of evolving mild

to moderate RDS requiring

treatment with nCPAP of 5–8

cmH2O and supplemental FiO2 of 0.22–0.30 to target SpO2

86%–94%.

Surfactant nebulisation ↓ need of intubation/72 hours:

11 /32 failure in nebulized + CPAP group

22/32 CPAP alone

Relative Risk (95% CI)=0.526 (0.292 to 0.950).

The reduced requirement for intubation was limited to the

32+0– 33+6 weeks’ GA stratum.

Results

How much surfactant is delivered into the alveoli? What is the optimal dose?

Respiratory Research 2019

mass mediandiameter, MMD = 3 μm

Is lower required lung dose due to improved surfactant distribution?

• Surfactant nebulised or instilled,

• 18 lung-lavaged rabbits

Dijk, Intensive care Med, 1997

• 2 h mechanical ventilation +CPAP

• Surfactant distribution using 99m technetium 99m la bel

The ongoing Chiesi CURONEB Study

Study objectives

• Part I

To assess the safety and tolerability of three single ascending doses of nebulized Curosurf®.

• Part II

To compare the efficacy of nebulized Curosurf®, administered at low dose (dose 1) or high dose (dose 2), during nCPAP, in terms of incidence of respiratory failure in the first 72 hours of life in spontaneously breathing preterm neonates with mild to moderate RDS.

EudraCT Number: 2016-004547-36 Sponsor Protocol Number: CCD-

01534CA1-01

Start Date*: 2017-03-16

Sponsor Name:Chiesi Farmaceutici S.p.A.

Full Title: A RANDOMIZED, OPEN, MULTINATIONAL, MULTICENTRE, 2-PART STUDY IN SPONTANEOUSLY BREATHING

PRETERM NEONATES WITH MILD TO MODERATE RESPIRATORY DISTRESS SYNDROME TO INVESTIGATE THE SAFETY,

TOLERABILITY ...

Medical condition: Mild to moderate respiratory distress syndrome

The ongoing Chiesi CURONEB Study

INCLUSION

1) 28+0 < GA < 32+6 (weeks+days)

2) Mild to moderate RDS

3) spontaneously breathing and stabilized on nCPAP within 1h

- Receiving CPAP 5-8 cmH2O and

- FiO2 0.25 and 0.40 to SpO2 88-95% for 30 min

EXCLUSION

1) Early need on intubation for resuscitation or within 1 h from

birth because of severe RDS

2) Respiratory distress not secondary to RDS

3) Surfactant before study or need of ET administration drugs

4) Severe birth asphyxia (e.g. APGAR score ≤ 5 at 10min or need for resusc. at 10

min, altered neurological state or neonatal enchephalopaty)

5) Major congenital anomalies 6) Rupture of the membranes > 21 days 7) Air-leak identification prior to the study

8) IVH ≥ III grade

9) Hypotension or hemodynamic instability requiring

pharmacological intervention

10) Any condition that, in the opinion of the Investigator, would

place the neonate at undue risk

11) Participation in another clinical trial of any placebo

REDOSING OPTION After 3 H from the beginning of the nebulisation

If presenting a sutained FiO2 0.25 and 0.40 to SpO2 88-95% for 30 min

Pari e eFlow System

The CURONEB – Part I

ISMB : Independent Safety Monitoring Board

The Curoneb - Part II

Active

Control (nCPAP)

Active

N = 84

N = 84

N = 84

2 years FU

Dose 1 (selected from Part I)

Dose 2 (selected from Part I)

nCPAP

36 weeks PMA

200mg/kg

400mg/kg

Recruitment overview

Final TARGET

(31Dec2019)

Actu

al

% target

EU 256 114 45

ITA 41 39 95

New option: Atomized Surfactant

Courtesy of Ilaria

Milesi

Atomized Surfactant: studies objectives

Courtesy of Ilaria

Milesi

Ped Res 2016

PCCM 2017

Ped Res 2019

Ped Res 2019

Conclusions • Preclinical studies on surfactant deficient animal models demonstrated

a significant respiratory function improvement despite the small doses of surfactant deposition into the lung and

a more homogeneous lung distribution

• The first pilot clinical studies in humans showed adequate safety and tolerability

• The development of new, customized MeSH nebulizer may further enhance the success of effective inhaled surfactant administration

Conclusions

• Nebulised/(atomised) surfactant still represents a promising method for effective surfactant delivery during spontaneous breathing

• Further work is also required to optimize some key aspects for minimally invasive surfactant delivery:

• Device (MeSH vs capillary aerosol generator vs atomiser)

• Interface (nasal prongs vs laryngeal mask vs pharyngeal tube) • Dose (200 mg? 400 mg? more? Repeated doses? Redosing intervals?)

• Redosing strategy (dose, timing, frequency, criteria)

• Strategy to enhance distribution (positioning??)

• Compared to nebulisation, surfactant atomisation may promote a higher deposition into the lungs, which deserves further investigations.

Thank you!!