Surfactant Replacement

Therapy
 Overview
Physiology Therapy
• What is Surfactant • What are preparations
• Development • Indications & Contra ?
• Synthesis • What to give ?

• Composition • When to give ?

• Role
• How many times?
• Complications
• Effects
• Limitations
• Clinical Benefits
• “Surfactant” are surface active materials that
lowers surface tension

• Surfactant pool size:

– Infants with RDS: 2-10 mg/kg body wt
– Increases over 4-5 days to term levels
– Term infants: 100 mg/kg body wt
 Development(milestones)
• 1929- Von Neergaards – surface tension contributes to lung recoil

• 1947-Gruenwald – lungs of still born have high surface tension

• 1959- Avery and Mead dem, RDS is due to surfactant def

• 1972- Robertson used natural surfactant in preterm rabbits

• 1980- Fujiwara dem. first successful use of surfactant in humans

Synthesis of Surfactant
A mature LB consists of a limiting membrane
surrounding about 20-70 tightly packed PL bi-
layers, or lamellae, arranged in a hemisphere

The phospholipids and proteins of Sf are

synthesized in type II cells, assembled in LB and
extruded into the alveolar lumen by exocytosis
 Surfactant Proteins

SP A is important or formation of
tubular lattice and recycling

SP-B and SP-C, are essential for

the uniform spreading and
adsorption (hydrophobic)

SP C def is not assoc. with resp

failure but may lead to interstitial
lung d in childhood.

SP-D plays role in host defense

apart from help in reuptake
 Composition Surfactant

• Phospholipids 85%
Saturated
Phosphatidylcholine 50%
Unsaturated
Phosphatidylcholine 20%
Phosphatidylglycerol and
Phosphatidylinositol 15%

• Protein 88%
• Neutral Lipids 8%
DPPC is the principal surface-active component of pulmonary surfactant and can
therefore be used as a relatively specific marker of surfactant metabolism.
Effect of surfactant proteins
 Role of Surfactant
Inspiration Expiration

SF +

SF -
 Effects of surfactant
EFFECT CAUSE
Stabilizes alveoli of different Without Sf, Pr will be ↑ in
sizes smaller alveoli which would
collapse into larger alveoli

Increases FRC Improved deflation stability and

longer expiratory time constant
• Improves oxygenation
Improves Oxygenation Reversal of atelectasis and
• improvement of V/Q matching

CO2 elimination, and Improvement in compliance

ventilatory support variables
PV loop:
Sf facilitates inflation of the lung from a ↓ Pr ( ),
permits the lung to open to a higher volume, and prevents
the lung from collapsing when pr is ↓ ( ).
 Benefit of surfactant therapy

• Decreased incidence / severity of RDS

• Increased survival from RDS
• Decreased need for oxygen
• Decreased ventilator support
• Decreased pneumothorax / PIE
• Decreased incidence & severity of CLD

Cochrane Database of Systematic Reviews 2007

 THERAPY
• What are preparations
• Indications & Contra ?
• What to give ?
• When to give ?
• How many times?
• Complications
• Limitations
 Preparations
Surfactant Preparation Generic Name Dose
Natural Lung mince Beractant Survanta 25 mg/ml
DPCC extract (Bovine) 4 ml/kg
PL (100MG/KG)
SP-B, SP-C (4/8 ml)
SP A(?) Poractant-α Curosurf 80 mg/ml
(Porcine) 2.5 or 1.25
ml/kg
100-200MG/KG
(2.5/1.5ml)
Lung Lavage Bovine lipid Neo surf 27 mg/ml
Extract extract 5ml/kg
(5 & 3 ml)
Synthetic Old DPCC, PG Exosurf (Colfosceril)
(Protein Free) (7:3 ratio) Pumactant (ALEC), 5ML/KG
New Has SP-B mimic Lucinactant (Surfaxin)
(Protein Analogue) KL4 Peptide 5.8ML/KG
Venticute(pr c)
 WHAT TO GIVE

BEST TYPE OF SURFACTANT THEREPY

 Natural surfactant extract versus synthetic surfactant for neonatal
respiratory distress syndrome(11 RCTs)

Significant reduction in the risk of

Pneumothorax (typical RR 0.63, 95% CI 0.53, 0.75)

Mortality (typical RR 0.87, 95% CI 0.76, 0.98)

Natural surfactant is associated with a marginal increase in the risk of IVH

(typical RR 1.09, 95% CI 1.00, 1.19) but no increase in grade 3 to 4 IVH

The meta-analysis supports a marginal decrease in the risk of BPD or mortality

(typical RR 0.95, 95% CI 0.90, 1.01)

• Soll R, Blanco F, Cochrane Review 2009

 SELECT Trial (Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial)
Moya FR, Gadzinowski J, Bancalari E et al

A multicenter, randomized, trial of lucinactant, colfosceril palmitate, and beractant for the
prevention of RDS among very preterm infants.

• Lucinactant reduced significantly the incidence of RDS at 24 hours, compared with

colfosceril (39.1% vs. 47.2%; OR: 0.68, 95% CI 0.52, 0.89)

No significant difference in comparison with beractant (33.3%)

• BPD at 36 weeks postmenstrual age was significantly less common with lucinactant
than with colfosceril (40.2% vs. 45.0%; OR: 0.75, 95% CI 0.56, 0.99)

• All-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant
than with beractant (21% vs. 26%; OR: 0.67, 95% CI 0.45, 1.00)

Pediatrics. 2005 Apr;115(4):1018-1029

 STAR Trial (Surfaxin Therapy Against Respiratory Distress Syndrome)
Sinha SK, Lacaze-Masmonteil T, Valls i Soler A, et al.

A multicenter, randomized, controlled trial

lucinactant poractant
At 28 days, survival w/o 37.8%, 33.1%
BPD

At 36 weeks 64.7% 66.9%

Mortality rate at 28 11.8% 16.1%

days

Mortality rate at 36 16% 18.5%

weeks

No significant differences were observed in the incidences of common complications of prematurity,

including IVH, PVL
Colfosceril palmitate etc
Pediatrics Vol. 115 No. 4 April 2005, pp. 1030-1038
Colfosceril palmitate etc
Protein containing synthetic surfactant versus animal derived surfactant
extract for the prevention and treatment of respiratory distress syndrome
(2RCT)

No significantly different risk of prespecified primary outcomes

Mortality at 36 weeks (typical RR 0.81, 95% CI 0.64, 1.03)

CLD at 36 weeks (typical RR 0.99, 95% CI 0.84, 1.18)

Combined outcome of mortality or CLD at 36 weeks (typical RR 0.96, 95% CI 0.82, 1.12)

There were also no differences in any of the secondary outcomes regarding

complications of prematurity except NEC

Decrease in the risk of NEC in infants who received protein containing synthetic
surfactants (typical RR 0.60, 95% CI 0.42, 0.86)

Pfister RH, Soll R, Wiswell TE, Cochrane Review 2009

WHEN TO GIVE
 Timing of surfactant administration

PREVENTION TREATMENT

Prophylactic Early
Rescue Late
Rescue
A suggested protocol would be to treat
babies ≤26 weeks’ gestation when Fi O2
requirements >0.30 and babies >26 weeks’
when Fi O2 requirements >0.40

Delivery room ??? …. <15 min < 2 hours …< 6 hours……..<48 h

 Prophylactic SFT
Author Title Outcomes Significance
affected
Soll R, ,2009 Prophylactic natural Pneumothorax 0.35 [0.26, 0.49]
ISSUE 3 surfactant extract for Neonatal mortality 0.60 [0.44, 0.83]
(CR) preventing BPD 0.84 [0.75, 0.93]
morbidity and or death
mortality in preterm
infants

Soll R,2009 Prophylactic synthetic Neonatal mortality 0.67 [0.50, 0.90]

Issue3 surfactant for Pneumothorax 0.70 [0.58, 0.85]
(CR) preventing morbidity
and mortality in
preterm infants
 SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network
Early CPAP versus surfactant in extremely preterm infants

1316 infants
24 0/7 weeks to 27 6/7 weeks
Randomly assigned to intubation and prophylactic surfactant
treatment or CPAP treatment in the delivery room

• Primary outcome was Death or BPD

RESULTS: • No significant difference in primary outcome between

CPAP group (47.8%) and surfactant group (51.0%)

• CPAP group patients had less frequent intubation or postnatal steroid

for BPD

N Engl J Med. 2010 May 27;362(21):1970-9

• The Vermont Oxford Network Delivery Room Management Trial (n = 648)

• Randomly assigned infants born at 26 to 29 weeks’ gestation to 1 of 3 treatment

groups:
– prophylactic surfactant and continued ventilation,
– prophylactic surfactant and rapid extubation to CPAP (INSURE),
– or nasal CPAP without surfactant.

• When compared with the group of infants receiving prophylactic surfactant and
continued ventilation, the RR of death or BPD was 0.78 (95% CI 0.59–1.03) for the
INSURE group and 0.83 (95% CI 0.64–1.09) for the CPAP group.

• However, in the nasal CPAP group, 48% were managed without intubation and 54%
without surfactant treatment.
 Prophylactic versus selective use of surfactant in preventing morbidity and mortality in
preterm infants

Cochrane Database of Systematic Reviews

14 MAR 2012 DOI: 10.1002/14651858.CD000510.pub2
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000510.pub2/full#CD000510-fig-00101
• The benefits of prophylactic surfactant on mortality (RR 0.89; 95%
CI 0.76–1.04) and air leak (RR 0.86; 95% CI 0.71–1.04) could no
longer be demonstrated.

• infants receiving prophylactic surfactant had a higher incidence of

BPD or death than did infants stabilized on CPAP
(RR 1.12; 95% CI 1.02–1.24)
• Should rescue be early or late ?
A recent meta-analysis (6RCT) of early (within 2 hours) versus delayed surfactant
treatment concluded that the

Risks of mortality (RR 0.84; 95% CI 0.74–0.95),

Air leak (RR 0.61; 95% CI 0.48–0.78),

Chronic lung disease (RR 0.69; 95% CI 0.55–0.86), and

Chronic lung disease or death (RR 0.83; 95% CI 0.75–0.91) were significantly
decreased.

There were no differences in other complications of prematurity

Bahadue FL.Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress
syndrome. Cochrane Database Syst Rev. 2012;11(11):CD001456
 Early Administration of Surfactant Followed by Brief Ventilation and Extubation to
CPAP (INSURE Strategy)

• The Vermont Oxford Network Delivery Room Management Trial (n = 648)

• randomly assigned infants born at 26 to 29 weeks’ gestation to 1 of 3 treatment

groups:
– prophylactic surfactant and continued ventilation,
– prophylactic surfactant and rapid extubation to CPAP (INSURE),
– or nasal CPAP without surfactant.

• When compared with the group of infants receiving prophylactic surfactant and
continued ventilation, the RR of death or BPD was 0.78 (95% CI 0.59–1.03) for the
INSURE group and 0.83 (95% CI 0.64–1.09) for the CPAP group.

• However, in the nasal CPAP group, 48% were managed without intubation and 54%
without surfactant treatment.

• A recent meta-analysis demonstrated that prophylactic surfactant (with rapid

extubation to CPAP) was associated with a higher risk of death or BPD (RR
1.12; 95% CI 1.02–1.24; number needed to harm of 17) when compared with early
stabilization with CPAP and selective surfactant administration.
 HOW MANY DOSES

• Repeated doses of surfactants given at intervals for predetermined indications

have decreased mortality and morbidity compared with placebo or single
surfactant doses.

• However, given the long half-life for surfactant in preterm infants with
RDS, redosing should not be needed more often than every 12 hours, unless
surfactant is being inactivated by an infectious process, meconium, or blood.

• Administering more than three doses has not been shown to have added benefit

Soll,R, OzekE. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal
respiratory distress syndrome. Cochrane Database Syst Rev. 2009;(1):CD000141pmid:19160177
• Method of Administration
 BOLUS/INFUSION
• A small clinical trial of human preterm infants showed no significant differences
in clinical outcomes between methods.

• During surfactant administration, reflux into the endotracheal tube occurred

more often when the infusion technique was used.

• Because data are conflicting and limited, the optimal method of surfactant
administration in preterm infants has yet to be clearly proven.

• Additionally, there is insufficient evidence to recommend the optimal number of

fractional doses of surfactant or what body position is best when surfactant is
administered.
 Less invasive surfactant administration is associated with improved
pulmonary outcomes in spontaneously breathing preterm infants.

Infants receiving LISA, who were born before 32 gestational weeks and
enrolled in the German Neonatal Network, were matched to control

Between 2009 and 2012, 1103 infants were treated with LISA at 37 centres.

LISA infants had

• lower rates of mechanical ventilation (41% versus 62%, p < 0.001),
postnatal dexamethasone treatment (2.5% versus 7%, p < 0.001),
• BPD (12% versus 18%, p = 0.001) and
• BPD or death (14% versus 21%, p < 0.001) than the controls.

Surfactant treatment of spontaneously breathing infants was associated with

lower rates of mechanical ventilation and BPD.

Additional large-scale randomised controlled trials are needed

Göpel W, Kribs A, Härtel C, Avenarius S, Teig N, Groneck P, Olbertz D, Roll C, Vochem

M, Weller U, von der Wense A, Wieg C, Wintgens J, Preuss M, Ziegler A, Roth B, Herting
E; German Neonatal Network (GNN).
 Minimally-invasive surfactant therapy in preterm infants on continuous
positive airway pressure.

For infants at 25-28 weeks gestation,

need for intubation <72 h was diminished after MIST compared with
controls (32% vs 68%; OR 0.21, 95% CI 0.083 to 0.55),

At 29-32 weeks (22% vs 45%; OR 0.34, 95% CI 0.11 to 1.1).

Duration of ventilation and incidence of bronchopulmonary dysplasia were

similar, but infants receiving MIST had a shorter duration of oxygen
therapy.
 Method of Administration
• Rapid instillation
• Slow instillation
• Dual lumen tube– Valls-i-Soler et al, Pediatrics 1998
• Nebulisation – Berggren et al, Acta Paediatr 2000
• INSURE – Verder et al, Pediatrics 1999
• Pharynx – Kattwinkel et al, J Perinatol, 2004
• Laryngeal mask – Trevisanuto et al, Biol Neonate 2005
• LIST/ MIST : The SF delivered to a spontaneously
breathing neonate with a catheter without intubation

Pharynx – Kattwinkel et al, J Perinatol, 2004, LMA – Trevisanuto , Biol Neonate 2005,
Gastric tube – Herting et al, AMV Trial Lancet 2011 : Angela Kribbs
 Post Surfactant Administration

Concerns after SRT No response

– Acute airway obstruction (ETT • Lung injury prior to birth
may get occluded):
bradycardia, cyanosis, ↓ BP • Lung injury after birth
• Risk of pulmonary trauma / and prior to treatment
hemorrhage
– Rapid improvement in • Pulmonary hypoplasia
oxygenation and ventilation
(be ready to wean rapidly)
• Cardiovascular disease
• Changes in cerebral perfusion
• Immunologic concerns
INDICATIONS OF SURFACTANT THEREPY

X ray
Early onset of
suggestive of
Preterm RD (Intubated
HMD ( NOT
with ↑ Fio2)
Mandate)

MAS, Congenital pneumonia, Pulmonary hemorrhage, BPD, ,

ARDS, Bronchiolitis
 CONTRAINDICATIONS OF SURFACTANT THEREPY

• NO absolute contraindication for SRT

• Major cong anomalies, incompatible with life

and PT neurologically devastated may be a
relative contraindication

• SRT may be abandoned in extreme PT

neonates (eg. <26 GA) after a thorough
discussion with the parents/caregivers about
the chance of morbidity free survival and the
social and economic impact
• NNF CPG 2010
 TAKE HOME MESSAGE

• Surfactant replacement, given as prophylaxis or rescue

treatment, reduces the incidence of RDS, air leaks, and mortality
in preterm infants with RDS

• Both animal-derived and newer synthetic surfactants with SP-B–

like activity decrease acute respiratory morbidity and mortality in
preterm infants with RDS.

• Early rescue surfactant treatment (<2 hours of age) in infants

with RDS decreases the risk of mortality, air leak, and chronic
lung disease in preterm infants.

• Early initiation of CPAP with subsequent selective surfactant

administration in extremely preterm infants results in lower rates
of BPD/death when compared with treatment with prophylactic
surfactant therapy.
• Surfactant treatment improves oxygenation and reduces the need for ECMO
without an increase in morbidity in neonates with meconium aspiration
syndrome

• Surfactant treatment of infants with congenital diaphragmatic hernia does not

improve clinical outcomes

• Preterm infants born at <30 weeks’ gestation who need mechanical ventilation
because of severe RDS should be given surfactant after initial stabilization

• Using CPAP immediately after birth with subsequent selective surfactant

administration should be considered as an alternative to routine intubation with
prophylactic or early surfactant administration in preterm infants

• Rescue surfactant may be considered for infants with hypoxic respiratory

failure attributable to secondary surfactant deficiency (eg, pulmonary
hemorrhage, meconium aspiration syndrome, or sepsis/pneumonia)
Thanks