Alexandria Egypt Rds 04-09

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 – SP-A Innate immunity – SP-D

PG PL

chol protein

PC

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 SHOICHI CHIDA YOSHITANE WATABE

HARUO MAETA TOMOAKI MORITA TADAAKI ABE

Departments of Paediatrics, Anaesthesiology, and Surgery, Akita University School of Medicine, Akita, Japan Lancet, 1980

Premature rabbits with RDS 25

VT ( ml / kg )

20 15

Phospholipids + Apoproteins

10

Phospholipids

5

Controls

5 25

10 25

T Curstedt, B Robertson, Eur J Biochem 1987

15 25

20 20

25 15

30 Time(min) 25 PIP(cmH2O)

Natural Surfactant-Preparations (1% SP-B, SP-C) bovine Surfactant TA Survanta Infasurf (CLSE) Alveofact porcine Curosurf

Phospholipids 88 % 84 % 95 % 88 % 99 %

Synthetic surfactant preparations ALEC

DPPC, PG

Exosurf

DPPC Hexadecanol Tyloxapol

Lucinactant (Surfaxin)

Phospholipids KL4

DPPC : dipalmitoylphophatidylcholine PG : phosphatidylglycerol KL4 ( sinapultide) peptide : synthetic hydrophobic 21-aminoacid

Acute effects of surfactant replacement improvement in oxygenation improvement in ventilatory requirement

15 14 13

0.8 0.7 0.6 0.5

**** ** ** 0.4 0.3

0.2 0

Mean airway pressure (cmH2O)

Fraction of inspired oxygen (FiO2)

0.9

Control Curosurf

1

2

3

4

5

6

12 11 * 10 ** ** 9 8 7 6 0 0 1

Days after treatment

Collaborative European Multicenter Study Group, Pediatrics 1988

* p<0.01 ** p<0.001 2

3

4

5

Days after treatment

6

Collaborative European Multicenter Study Group - Randomized Control Trial Complications

Control  n=69

Curosurf  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

Pediatrics. 1988;82:683–691.

*P <0.05; **P <0.01

Natural Surfactant vs Control Prophylaxis Trials

Treatment Trials

Pneumothorax IVH PDA BPD Mortality Death or BPD

0

0.5

1

1.5

2 0

Odds ratio

0.5

IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia Speer CP, Halliday HL , Curr Pediatr. 1994;4:5–9. 

1

1.5

2

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 STUDY

Decreased Risk 0.2 0.5 1.0

Increased 2.0 4.0

Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 Bevilacqua 1997 TYPICAL ESTIMATE 0.2 Soll 2001

0.5 1.0 2.0 4.0 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 STUDY

Decreased Risk 0.2 0.5 1.0

Increased 2.0 4.0

Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 TYPICAL ESTIMATE 0.2 Soll 2001

0.5 1.0 2.0 4.0 Relative Risk and 95% CI

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

* Egberts et al, Pediatrics 1997;

0.5

1

Odds Ratio

** Walti et al, Biol Neonate 2002

1.5

2

Comparison of mortality after prophylactic and rescue surfactant therapy in infant of <30 weeks of gestation

Survival (%)

100

rescue prophylactic

Soll R, Biol Neonate, 1998

80 60 40 20 0

24

25

26

27

28

29

Gestational age (weeks)

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 n=86

Late 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 n=176

Multiple doses n=167

Pneumothorax

18%

9%**

Mortality

21%

13%*

Survival without BPD

67%

73% *p < 0.05

Speer et al, Pediatrics 1992

** < 0.01

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

60 10 MABP

40

5

20 PaCO2 0 0

Minutes

120

0

PaCO2 kPa

SaO² % MABP, mm HG

15

Surfactant Bolus vs Slow Infusion in Rabbits 140

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

sysBP (mmHg)

120 100 80 Bolus (200 mg/kg, n=6) 60 40 20

0

2

5

10

15

20

30

40

min after surfactant instillation Segerer et al, Pediatr Res 1993

50

60

Surfactant Bolus vs Slow Infusion in Rabbits 600 Bolus (200 mg/kg, n=6) 500

PaO2 (mmHg)

400 300 200 Infusion 44` (200 mg/kg, n=4)

100 0

0

2

5

10

15

20

30

40

min after surfactant instillation Segerer et al, Pediatr Res 1993

50

60

Curosurf instillation: first minute 5s

10 s

15 s

20 s

40 s

50 s

10 s

25 s Ingimarsson et al, Biol Neonate, 2000

30 s

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

OUTCOME (# studies)

Need for MV (5) Airleak (4)

Early Selective Decreased Risk Increased Surfactant Surfactant n=322

n=312

37%

56%

4%

8%

1%

3%

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

6%

Mortality

(3)

Surfactant Use (5)

100%

Cochrane Controlled Trial Register (2005)

0.2

0.5

1.0

2.0

4.0

0.2

0.5

1.0

2.0

4.0

63% 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

0 Halliday HL. Drugs. 1996;51:226–237.

Favors synthetic

1 Odds ratio

2

Comparison of Pumactant(Alec) and Poractant alfa(Curosurf) in Neonates at 25–29 Weeks’ Gestation Pumactant  (n=100)

Poractant alfa  (n=99)

31%

14%*

Mortality *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 Treatment trials 3

1,2

n = 1.123 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 FiO2

0.8 = Curosurf = Survanta

0.7 0.6 0.5

*

0.4

**

0.3 0.2

0

1

Speer et al, Arch Dis Child 1995

2

3

4 5 6 Time (days)

7

8

9

10 * p<0.5 ** p<0.01

Curosurf vs. Survanta – Rescue Trial (3)

PIE

Curosurf (n= 33) 3%

Survanta (n = 40) 10 %

PTX

6.1 %

12.5 %

IVH Total

21.2 %

35 %

3%

12.5 %

12.5 %

11.4 %

3%

12.5 %

IVH Gr. III-IV O2 at 36 wks PCA Mortality

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 200mg/kg

Ramanathan R et al. , Am J Perinatol 2004

Curosurf 100mg/kg

Survanta 100mg/kg

Meta-Analysis Curosurf vs Survanta Mortality RESCUE TRIALS Speer 1995 Chrishanti 1999* Ramanathan 2004 Ramanathan 2004* Nicoski 2003 Baroutis 2005 32/302(10,5%)

CUROSURF SURVANTA 1/33 5/40 5/17 3/10 3/99 8/98 6/96 8/98 0/30 2/30 5/27 6/26 20/302 (6,7%) OR 0.55

Halliday, Biol Neonate 2005

(0.31-0.98 CI) * 100 mg/kg Curosurf

CUROSURF vs. SURVANTA Effect on Mortality Outcome

MORTALITY (5)

Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 -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 neurological 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