2nd International Neonatology Conference

April 2 - 4, 2009 Alexandria, Egypt

European Experience with

Surfactant Replacement Therapy in Neonatal RDS

Bengt A. Robertson
A Pioneer and Leader in Surfactant Research
* September 14, 1935, Stockholm
† December 7, 2008, Stockholm

Prof. Christian P. Speer, MD, FRCPE,

Director and Chairman, University Children’s Hospital Würzburg, Germany
 Epidemiology of RDS

● Major cause of morbidity in very preterm

infants
● About 1 % of live births
● 30.000 - 40.000 cases annually in USA
● Antenatal steroids reduce incidence and
severity of RDS
● RDS develops in approximately 50 % of
infants 24 - 30 wks & 25 % infants > 30 wks
 Composition of Human
Surfactant
• Phospholipids: various fractions
• Apoproteins PG PL
chol

– SP-A protein

Innate immunity PC

– SP-D
DPPC

– SP-B Adsorption and

– SP-C spreading of phospholipids
 Milestones in Neonatology
Sweden 1972
Enhörning G, Robertson B, Lung Expansion in Premature Rabbit
Fetuses after Tracheal Deposition of Surfactant
Pediatrics 1972;50:58-66

Pressure volume curves

representing mean volumes
of air entering lungs at
various inflation and
deflation pressures (first
expansion cycle).
Surfactant-treated fetuses
show a wide, mature type
of hysteresis loop, which is
clearly different from that of
saline-treated controls.
 Milestones in Neonatology

Control Surfactant
Histological appearance of lungs from saline-treated control fetuses (A) and
surfactant-treated fetuses (B).
Enhörning, Robertson, Pediatrics 1972, 50, 58-66
 Milestones in Neonatology

ARTIFICIAL SURFACTANT
THERAPY IN HYALINE-MEMBRANE
DISEASE
TETSURO FUJIWARA HARUO MAETA
SHOICHI CHIDA TOMOAKI MORITA
YOSHITANE WATABE TADAAKI ABE

Departments of Paediatrics, Anaesthesiology,

and Surgery,
Akita University School of Medicine, Akita, Japan

Lancet, 1980
 Premature rabbits with RDS
25

20
VT ( ml / kg )

Phospholipids
15 + Apoproteins

10 Phospholipids

5 Controls

5 10 15 20 25 30 Time(min)
25 25 25 20 15 25 PIP(cmH2O)

T Curstedt, B Robertson, Eur J Biochem 1987

Natural Surfactant-Preparations
(1% SP-B, SP-C)
bovine Phospholipids
Surfactant TA 88 %
Survanta 84 %
Infasurf (CLSE) 95 %
Alveofact 88 %
porcine
Curosurf 99 %
 Synthetic surfactant preparations

ALEC DPPC, PG
Exosurf DPPC
Hexadecanol
Tyloxapol

Lucinactant Phospholipids
(Surfaxin) KL4

DPPC : dipalmitoylphophatidylcholine
PG : phosphatidylglycerol
KL4 ( sinapultide) peptide : synthetic hydrophobic 21-aminoacid
 Acute effects of
surfactant replacement
improvement in oxygenation
improvement in ventilatory
requirement
 Control
Curosurf

Mean airway pressure (cmH2O)

Fraction of inspired oxygen (FiO2)

0.9 15
0.8 14
13
0.7 12
0.6 11 *
10 ** **
0.5 9
**** **
**
0.4 8

0.3
7 * p<0.01
6
** p<0.001
0.2 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Days after treatment Days after treatment

Collaborative European Multicenter Study Group, Pediatrics 1988

 Collaborative European Multicenter Study Group
- Randomized Control Trial -

Control  Curosurf 
Complications n=69 n=77
PIE 27 (39%)  18 (23%)*
Pneumothorax 24 (35%)  14 (18%)*
ICH 38 (55%)  36 (47%)
BPD 18 (26%) 12 (16%)
Mortality 35 (51%)   24 (31%)*
Survival without BPD 18 (26%)    42 (55%)**
PIE, pulmonary interstitial emphysema; ICH, intracerebral
hemorrhage; BPD, bronchopulmonary dysplasia *P <0.05; **P <0.01
Pediatrics. 1988;82:683–691.
 Natural Surfactant vs Control
Prophylaxis Trials Treatment Trials
Pneumothorax

IVH

PDA

BPD

Mortality

Death or BPD

0 0.5 1 1.5 2 0 0.5 1 1.5 2

Odds ratio
IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus;
BPD, bronchopulmonary dysplasia

Speer CP, Halliday HL , Curr Pediatr. 1994;4:5–9. 
 Factors influencing therapeutic
response of surfactant treatment

initial dose
timing
multiple doses
mode of surfactant application
surfactant preparations
 Initial dose of natural
surfactants:

~ 100 mg/kg bodyweight

 TIMING OF SURFACTANT
ADMINISTRATION
PROPHYLACTIC SURFACTANT ADMINISTRATION

ADVANTAGES:
• Improved distribution
• Decreased barotrauma

DISADVANTAGES:
• Need for aggressive resuscitation practice
• Increased utilization/cost
 DELIVERY ROOM vs. TREATMENT SURFACTANT
Randomized Controlled Trials, n=8
Number Of Enrolled Infants and Gestational Age, n=2816

EFFECT ON NEONATAL MORTALITY

Decreased Risk Increased
STUDY
0.2 0.5 1.0 2.0 4.0

Kendig 1991
Dunn 1991
Egberts 1993
Kattwinkel 1993
Walti 1995
Bevilacqua 1996
Bevilacqua 1997

TYPICAL ESTIMATE

0.2 0.5 1.0 2.0 4.0

Soll 2001 Relative Risk and 95% CI
 DELIVERY ROOM vs. TREATMENT SURFACTANT
Randomized Controlled Trials, n=8
Number Of Enrolled Infants and Gestational Age, n=2816

EFFECT ON PNEUMOTHORAX
Decreased Risk Increased
STUDY
0.2 0.5 1.0 2.0 4.0

Kendig 1991
Dunn 1991
Egberts 1993
Kattwinkel 1993
Walti 1995
Bevilacqua 1996

TYPICAL ESTIMATE

0.2 0.5 1.0 2.0 4.0

Relative Risk and 95% CI
Soll 2001
Prophylactic versus Rescue Treatment with Curosurf
Meta-Analysis of 3 Trials, n= 671*

decreased risk increased risk

Severe RDS

Mortality

CLD

ICH**
total

severe
0 0.5 1 1.5 2
Odds Ratio
* Egberts et al, Pediatrics 1997; ** Walti et al, Biol Neonate 2002
 Comparison of mortality after prophylactic and rescue
surfactant therapy in infant of <30 weeks of gestation
100

Survival (%) 80

60

40

rescue 20

prophylactic
0
24 25 26 27 28 29
Gestational age (weeks)
Soll R, Biol Neonate, 1998
 The „Early versus late treatment“ trial (n=182)
Singel dose treatment with Curosurf (200mg/kg)

early treatment FiO2 0.4-0.59

late treatment FiO2 > 0.6

Bevilacqua et al, J Perinat Med, 1993

The „Early versus late treatment“ trial (n=182)
Complications

Treatment Early Late

n=86 n=96

Intracerebral
hemorrhage grade III-IV 7,0 % 17,9 % *

Mortality 9,3 % 22,9 % *

* p < 0.05
Bevilacqua et al, J Perinat Med, 1993
 Collaborative European Multicenter Study Group
- Single versus multiple doses - (1988 - 1990)

Complications Single dose Multiple doses

n=176 n=167

Pneumothorax 18% 9%**

Mortality 21% 13%*

Survival without BPD 67% 73%

*p < 0.05 ** < 0.01

Speer et al, Pediatrics 1992
 Curosurf 4 Trial

Up to 300 mg/kg Curosurf is

as good as up to 600 mg/kg when
28 days outcome is assessed.

Halliday et al., Arch Dis Child, 1993

 100 20

SaO2
80
15
SaO² % MABP, mm HG

60

PaCO2 kPa
10
MABP
40

5
20
PaCO2

0 0
0 120
Minutes
 Surfactant Bolus vs Slow Infusion in Rabbits
140
Infusion 44` (200 mg/kg, n=4)

120

100
sysBP (mmHg)

80
Bolus (200 mg/kg, n=6)
60

40

20
0 2 5 10 15 20 30 40 50 60
min after surfactant instillation
Segerer et al, Pediatr Res 1993
 Surfactant Bolus vs Slow Infusion in Rabbits
600
Bolus (200 mg/kg, n=6)
500

400
PaO2 (mmHg)

300

200
Infusion 44` (200 mg/kg, n=4)

100

0
0 2 5 10 15 20 30 40 50 60
min after surfactant instillation
Segerer et al, Pediatr Res 1993
 Curosurf instillation: first minute
5s 10 s 15 s 20 s

10 s

25 s 30 s 40 s 50 s
Ingimarsson et al, Biol Neonate, 2000
Curosurf instillation: 2 - 24 min
2 min 4 min 6 min 8 min

8 min

12 min 16 min 20 min 24 min

 Randomized Comparison of Curosurf Dosing
Bolus versus dual-lumen instillation within 1 min, n=198

Bolus Dual-lumen instillation

Episodes of hypoxia 40% 18%

Efficacy +++ +++

Complications (+) (+)

Valls-i-Soler et al (Spanish Surfactant Coll. Group) Pediatrics 1998

 Surfactant Therapy and Nasal CPAP*

1 dose of Curosurf (200mg/kg)

Preterm infants with

moderate RDS on nasal CPAP

Reduced need of
subsequent mechanical ventilation

*Verder et al, N Engl J Med, 1994; Verder et al, Pediatrics, 1999

 INSURE
Results of Meta-analysis of 5 trials

Early Selective Decreased Risk Increased

Surfactant
Surfactant
OUTCOME (# studies)
n=322 n=312 0.2 0.5 1.0 2.0 4.0

Need for MV 37% 56%

(5)
Airleak (4) 4% 8%

Mortality (3) 1% 3%

BPD (oxygen at 28d) (3) 3% 6%

Surfactant Use (5) 100% 63%

0.2 0.5 1.0 2.0 4.0

Cochrane Controlled Trial Register (2005) Relative Risk and 95% CI

 Effects of Natural Surfactants
vs Colfosceril Palmitate(Exosurf)
7 randomized trials, 3756 preterm infants

0.52

Air leaks

0.8

Mortality

Favors natural Favors synthetic

0 1 2
Odds ratio
Halliday HL. Drugs. 1996;51:226–237.
 Comparison of Pumactant(Alec) and
Poractant alfa(Curosurf) in Neonates
at 25–29 Weeks’ Gestation

Pumactant  Poractant alfa 
(n=100) (n=99)

Mortality 31% 14%*

*P = 0.006

The trial was stopped early

Ainsworth et al. Lancet. 2000;355:1387–1392.

 Natural versus Natural Surfactant
- Infasurf versus Survanta -

Prophylaxis trials 1,2

n = 1.123
Treatment trials 3 n = 1.361

Results:
No differences in death or BPD or any variable

1
Bloom et al, Pediatrics 1997; 2Bloom et al, Pediatrics 2005; 3Bloom et al, Pediatrics 2005
 Curosurf vs. Survanta – Rescue Trial
Changes in FiO2
1.0
0.9
0.8
0.7 = Curosurf
FiO2

= Survanta
0.6
0.5 **
*
0.4
0.3
0.2
0 1 2 3 4 5 6 7 8 9 10
Time (days)
* p<0.5
Speer et al, Arch Dis Child 1995
** p<0.01
 Curosurf vs. Survanta – Rescue Trial (3)

Curosurf Survanta
(n= 33) (n = 40)
PIE 3% 10 %
PTX 6.1 % 12.5 %
IVH Total 21.2 % 35 %
IVH Gr. III-IV 3% 12.5 %
O2 at 36 wks PCA 12.5 % 11.4 %

Mortality 3% 12.5 %
No Difference in Death or BPD
Speer et al. Arch Dis Child 1995
 Curosurf vs Survanta
Effect on Neonatal Mortality
10%
9%
8%
7%
6%
5%
4%
3%
2%
1%
0%
Curosurf Curosurf Survanta
200mg/kg 100mg/kg 100mg/kg

Ramanathan R et al. , Am J Perinatol 2004

 Meta-Analysis Curosurf vs Survanta
Mortality

RESCUE TRIALS CUROSURF SURVANTA

Speer 1995 1/33 5/40
Chrishanti 1999* 5/17 3/10
Ramanathan 2004 3/99 8/98
Ramanathan 2004* 6/96 8/98
Nicoski 2003 0/30 2/30
Baroutis 2005 5/27 6/26
20/302 (6,7%)
32/302(10,5%)
OR 0.55 (0.31-0.98 CI)

Halliday, Biol Neonate 2005 * 100 mg/kg Curosurf

 CUROSURF vs. SURVANTA
Effect on Mortality
Risk Difference Decreased Risk Increased
Outcome ( 95% CI ) 0.2 0.5 1.0 2.0 4.0

MORTALITY (5) -0.05 (-0.09, 0.00)

CUROSURF 100 mg/kg (3) -0.02 (-0.10, 0.05)

CUROSURF 200 mg/kg (3) -0.07 (-0.12, -0.02)

0.2 0.5 1.0 2.0 4.0

Relative Risk and 95% CI

Halliday, Biol Neonate 2005

Surfactant Therapy - Recommendations
• Babies with or at high risk of RDS should be
given surfactant
• At least 100 mg/kg phospholipid is required and
200 mg/kg may be better for established RDS
• Administration by bolus results in better
distribution
• Prophylaxis reduces mortality and air leaks, but
more babies end up being treated
• Surfactant can be given whilst avoiding
mechanical ventilation using INSURE technique
• A second (and occasionally a third) dose is
sometimes required
Surfactant Therapy - Recommendations
• Natural surfactants preferred to synthetic
• Of natural surfactants the bovine products
beractant and calfactant seem similar in their
efficacy but poractant alfa in a dose of 200 mg/kg
for rescue leads to improved survival when
compared to beractant 100 mg/kg
• Where possible, duration of mechanical
ventilation should be shortened by immediate, or
early extubation to CPAP following surfactant,
provided the baby is stable
Natural surfactant preparations
Adverse effects

acute none

chronic no sensitation against

apoproteins
no differences in neuro-
logical long-term outcome
( treated / controls )
slow - virus infections ?
Conclusions: Surfactant Therapy
• First drug developed only for treatment of neonates
• Major breakthrough in neonatal medicine over the
past two decades
• Reduces both neonatal mortality in RDS and air leak
by approximately 50%
• About 6% reduction in overall infant mortality (in the
first year of life)
• No increase in pulmonary or neurodevelopmental
problems at long-term follow-up
• Highly cost - effective therapy
• Numerous potential applications currently under
investigation