Surfactant Replacement Therapy:Beyond RDS

Steven M. Donn, MD, FAAP

Professor of PediatricsChief, Neonatal-Perinatal Medicine

C.S. Mott Children’s HospitalUniversity of Michigan Health System

Pulmonary Surfactant

Multicomponent complex of several phospholipids, neutral lipids, and associated proteins

Synthesized and secreted by Type II epithelial cells within the lung

Reduces collapsing force in the alveolus, conferring stability and maintaining alveolar surface free of liquid

Efficacy of Surfactant Therapy

Demonstrated for both prophylaxis (within first few minutes of life) and rescue (after 2 hrs. and with signs of respiratory failure)

>40 trials and 20,000 enrolled infants40% reduction in odds of neonatal

death35-50% reduction in air leak

Other Neonatal Disorders with Surfactant Lack or Dysfunction

Term infants with respiratory failure

Meconium aspiration syndrome

Pulmonary hemorrhage

Pneumonia

Congenital diaphragmatic hernia

Early bronchopulmonary dysplasia

Other Pediatric Disorders with Surfactant Lack or Dysfunction

Bronchiolitis

ARDS

Cystic Fibrosis

Asthma

Chronic bronchitis

Otitis media

Surfactant and MAS

Surfactant Inhibitors in MAS

• Among infants with MAS, concentrations in lung fluid of total protein, albumin, and membrane-derived phospholipid are elevated

• Infants with MAS frequently have hemorrhagic pulmonary edema

• Surfactant therapy may mitigate these findings

*Dargaville PA, et al. J Pediatr 2001;138:113-115

Alveolus

Dilute

Surfactant

Dilute Surfactant Lavage

Surfactant and MAS

• Cochrane Review:Mortality: no significant effectPneumothorax/PIE: no significant effectDuration of PPV: no significant effectSupplemental oxygen at D/C: no sig.

effectChronic lung disease: no sig. effectNeed for ECMO: RR 0.64 (surfactant)Hospitalization: mean decrease of 8

days (surfactant)

El Shahed, Dargaville, Ohlsson, Soll

But…what about LAVAGE?

Lavage: [French, from the Latin lavo, to wash]. The washing out of a hollow cavity or organ by copious injections and rejections of fluid.

Portique de lavage

Surfaxin® Lavage Trial

Pilot trial of 22 infants with MAS15 treated by lavage, 7 controls (SOC)MAS, mechanical vent., OI 8-25Lavage procedure: 8 mL/kg dilute

Surfaxin per lung X2, then third lavage with concentrated Surfaxin

Wiswell TE. Knight GR, Finer NN, Donn SM, et al. Pediatrics 2002;109:1081

Lucinactant (Surfaxin®) is an investigational product not approved by the US Food and Drug Administration.

*Wiswell TE, et al. Pediatrics 2002;109:1081-1087.

Instill SurfaxinInstill Surfaxin®®

Conclusions

Trends toward faster weaning from mechanical ventilation (6.3 v. 9.9 days)

More rapid decline in OISafeWell tolerated

…but we can deal with it!

Bronchopulmonary Dysplasia

Affects 30-40% of infants <1500g

May result in severe respiratory compromise and growth and development

Some evidence for surfactant inadequacy during recovery phase of RDS

Carl Bose and Matthew LaughonUniversity of North Carolina, Chapel Hill, NC

Fernando R. MoyaNew Hanover Regional Medical Center, Wilmington, NC

Judy L. Aschner

Vanderbilt University Medical Center, Nashville, TN

Steven M. DonnUniversity of Michigan Health System, Ann Arbor, MI

Robert Segal, Carlos Guardia, and Genzhou LiuDiscovery Laboratories, Inc., Warrington, PA

for the Surfaxin® BPD Study Group

Late Treatment with a Synthetic Surfactant for the Prevention of Bronchopulmonary Dysplasia

* Lucinactant (Surfaxin®) is an investigational product not approved by the US FDA.

DisclosureThis study was funded by Discovery Laboratories.

Personnel employed by Discovery were directly responsible for:

• Protocol development

• Data management

• Statistical analysis

Authors not employed by Discovery were compensated for their efforts and were responsible for:

• Advice regarding protocol development

• Interpretation of results and preparation of presentation

Background

• Bronchopulmonary dysplasia (BPD) is the most frequent serious complication of preterm birth.

• Preterm infants requiring prolonged ventilation have surfactant dysfunction, presumably as a result of

lung inflammation

protein leak into air spaces

• Short-term improvement in lung function has been reported after surfactant administration in chronically ventilated infants.

Risk for BPD Relative to Oxygen Therapy

From Laughon et al. PAS abstract # 7935.9, 2007

Objective

• The purpose of this study was to estimate the effect of the administration of lucinactant after the first two days of life to extremely preterm infants at risk for developing BPD.

• We hypothesized that this treatment would reduce the incidence of death or BPD.

Methods

• Masked, multi-center, randomized, controlled trial

• Inclusion Criteria

Birth weight 600-900 grams

3-10 days of age

Mechanical ventilation and FiO2 ≥ 0.3

Early surfactant therapy, if indicated

• Exclusion CriteriaSevere lung disease

(FiO2 > 0.8 and mean Paw > 12 cm H2O)

Prolonged rupture of membranes Culture proven sepsis Severe IVH Major congenital anomalies Prior treatment with iNO or steroids

Methods

809 infants 600-900 grams

136 enrolled

47 Lucinactant 90 mg/kg 44 Placebo/sham air

673 not enrolled:574 Not eligible:185 not receiving mechanical ventilation93 FiO2 less than 0.3071 No informed consent46 FiO2 > 0.30 but less than 0.25 prior to

randomization42 Grade III/IV IVH22 Did not receive surfactant on DOL 121 FiO2 >0.8 and MAP >1215 ROM > 2 weeks14 Sepsis 11 Congenital malformation10 Another clinical trial/device6 Prior use of NO2 Prior use of corticosteroids99 Eligible, not enrolled:71 No informed consent 28 Not randomized within 8 hours of

meeting eligibility

45 Lucinactant 175 mg/kg

Derivation of Patient Population

Methods

• Stratified by center

• Randomized to three groups:

Lucinactant 175 mg TPL/kg BW (S-175)

(standard dose)

Lucinactant 90 mg TPL/kg BW (S-90)

Placebo (sham air)

• Up to 5 doses at 48 hour intervals

• No treatment after 18 days of age

Surfactant Preparation

Lucinactant*

• Phospholipids (30 mg/mL)

- Dipalmitoylphosphatidylcholine(22.5 mg/mL)

- Palmitoyl-oleoyl phosphatidylglycerol(7.5 mg/mL)

• KL4 peptide– 21 AA synthetic peptide

Results

• 136 infants enrolled from 12/2004 to 6/2006

• 34 centers

19 in the United States

5 in Chile

7 in Poland

3 in Hungary

Patient Characteristics by Group

Characteristic S-90 S-175 Placebo

Number 47 45 44

GA (wks; median) 25 26 26

BW (g; mean) 734 773 753

Gender (% male) 64* 53 39

Race (% white) 64 80 70

FiO2 at entry (median) 0.35 0.35 0.36

* p=0.016 vs. placebo

Supplemental Oxygen Requirement

First Dose

Peri-dosing Events

DOSE 1

S-90 S-175 Placebo

Dose interruption (%) 13 20 0

Desaturation* (%) 60 51 9

Bradycardia** (%) 21 13 0

* Desaturation = SaO2 < 75% for more than 30 seconds**Bradycardia = HR < 100 bpm for more than 30 seconds

Outcomes of Interest

S-90 S-175 Placebo

BPD (%) 49 47 50(O2 at 36 wks PMA)

Death (%) 30 11 16

Death or BPD (%) 79 58 66

4.94.3

1.7 1.8

0.80.5

0.3 0.3

1.91.5

0.7 0.7

0.1

1.0

10

S-90 vs. Placebo

Unadjusted Adjusted*

Od

ds

Rat

io

Unadjusted Adjusted*

S-175 vs. Placebo

Odds Ratios for Death or BPD

* adjusted for gestational age, birth weight, and gender

Number of Doses by Group

S-90 S-175 Placebo

1 dose (%) 100 100 100

2 doses (%) 87 89 89

3 doses (%) 72 73 77

4 doses (%) 60 60 66

5 doses (%) 55 44 66

Secondary Outcomes

No differences between either lucinactant treated group and placebo group in the incidences of:

• Air leak

• IVH

• PVL

• NEC

• ROP

Conclusions

• Treatment of infants at risk for BPD beginning after the first two days of life with a synthetic, peptide-containing surfactant :

Appears to reduce supplemental oxygen requirement for up to 48 hours after dosing

May reduce death or BPD among infants receiving 175 mg/kg TPL per dose

• These results justify a larger RCT to test efficacy.

Other Surfactant Ideas

Mix surfactant with non-ionic polymers (PEG, dextran) to reduce inactivation

Mix surfactant with perfluorochemicals

Use phospholipid analogues that improve reduction of surface tension and are more resistant to degradation

SP-A and SP-D analogues

Add to exogenous surfactants: 1) anti-inflammatory agents; 2) anti-proteases, and/or 3) anti-oxidants

•Polymyxin B sulfate is produced by the growth of Bacillus polymyxa

•It is a cyclic decapeptide

•Polymyxin B cross-links lipid vesicles in a manner similar to SP-B, although it is structurally unrelated to SP-B

•It exhibits in vitro surface activity similar to SP-B

•This suggests an avenue for identification of other SP-B analogues

Other Potential Uses of Surfactant

Surfactant could be a delivery vehicle for various medications:

Antimicrobials

Chemotherapy

Vasodilators

Bronchodilators

Bolus into lungs via an ETT

Bolus into the nasopharynx

Slow infusion

Aerosolized

Lavage

Optimal Method of Administration May Differ for Each Application

Got Got Surfactant!Surfactant!