Alexandria Egypt RDS 04-09

8/14/2019 Alexandria Egypt RDS 04-09

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Prof. Christian P. Speer, MD, FRCPE,

Director and Chairman, University Childrens Hospital Wrzburg, Germany

April 2 - 4, 2009 Alexandria, Egypt

2nd International Neonatology Conference

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


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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

Epidemiology of RDS


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Composition of Human

Surfactant

Phospholipids: various fractions

Apoproteins

SP-A

SP-D

SP-B

SP-C

Innate immunity

Adsorption and

spreading of phospholipids

DPPC

PC

PG PL

chol

protein


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Milestones in Neonatology

Sweden 1972Enhrning G, Robertson B, Lung Expansion in Premature Rabbit

Fetuses after Tracheal Deposition of SurfactantPediatrics 1972;50:58-66

Pressure volume curves

representing mean volumesof 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.


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Histological appearance of lungs from saline-treated control fetuses (A) and

surfactant-treated fetuses (B).

Enhrning, Robertson, Pediatrics 1972, 50, 58-66

Control Surfactant


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Lancet, 1980

ARTIFICIAL SURFACTANTTHERAPY IN HYALINE-MEMBRANE

DISEASETETSURO FUJIWARA

SHOICHI CHIDAYOSHITANE WATABE

HARUO MAETA

TOMOAKI MORITATADAAKI ABE

Departments of Paediatrics, Anaesthesiology,

and Surgery,

Akita University School of Medicine, Akita, Japan



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25 25 25 20 15 25

5 10 15 20 25 30

PIP(cmH2O)

Time(min)

5

10

15

20

25

VT(ml/kg)

T Curstedt, B Robertson, Eur J Biochem 1987

Phospholipids

+ Apoproteins

Phospholipids

Controls

Premature rabbits with RDS


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Natural Surfactant-Preparations

(1% SP-B, SP-C)bovine Phospholipids

Surfactant TA 88 %Survanta 84 %

Infasurf (CLSE) 95 %

Alveofact 88 %porcine

Curosurf 99 %


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Synthetic surfactant preparations

ALEC DPPC, PG

Exosurf DPPC

HexadecanolTyloxapol

DPPC : dipalmitoylphophatidylcholine

PG : phosphatidylglycerol

KL4 ( sinapultide) peptide : synthetic hydrophobic 21-aminoacid

Lucinactant

(Surfaxin)

Phospholipids

KL4


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Acute effects of

surfactant replacement

improvement in oxygenation

improvement in ventilatoryrequirement


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Collaborative European Multicenter Study Group, Pediatrics 1988

*

**

p


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Collaborative European Multicenter Study Group

- Randomized Control Trial -

Complications

PIE

Pneumothorax

ICH

BPD

Mortality

Survival without BPD

Controln=69

27 (39%)

24 (35%)

38 (55%)

18 (26%)

35 (51%)

18 (26%)

Curosurfn=77

18 (23%)*

14 (18%)*

36 (47%)

12 (16%)

24 (31%)*

42 (55%)**

Pediatrics. 1988;82:683691.

*P


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Treatment TrialsTreatment TrialsProphylaxis TrialsProphylaxis Trials

00 0.50.5 11 1.51.5 22 00 0.50.5 11 1.51.5 22

Speer CP, Halliday HL , Curr Pediatr. 1994;4:59.

PneumothoraxPneumothorax

IVHIVH

PDAPDA

BPDBPD

MortalityMortality

Death or BPDDeath or BPD

Odds ratioOdds ratio

Natural Surfactant vs Control

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


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Factors influencing therapeutic

response of surfactant treatment

initial dose

timing

multiple doses

mode of surfactant application

surfactant preparations


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Initial dose of naturalsurfactants:

~ 100 mg/kg bodyweight


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TIMING OF SURFACTANT

ADMINISTRATION

PROPHYLACTIC SURFACTANT ADMINISTRATION

ADVANTAGES:

Improved distribution Decreased barotrauma

DISADVANTAGES:

Need for aggressive resuscitation practice Increased utilization/cost


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Relative Risk and 95% CI

STUDY0.5 1.0 2.0 4.00.2

Decreased IncreasedRisk

0.5 1.0 2.0 4.00.2

DELIVERY ROOM vs. TREATMENT SURFACTANT

Dunn 1991

EFFECT ON NEONATAL MORTALITY

Egberts 1993

Kattwinkel 1993

Walti 1995

Bevilacqua 1996

Soll 2001

TYPICAL ESTIMATE

Kendig 1991

Bevilacqua 1997

Randomized Controlled Trials, n=8

Number Of Enrolled Infants and Gestational Age, n=2816


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STUDY0.5 1.0 2.0 4.00.2

Decreased IncreasedRisk

0.5 1.0 2.0 4.00.2

DELIVERY ROOM vs. TREATMENT SURFACTANT

Dunn 1991

EFFECT ON PNEUMOTHORAX

Egberts 1993

Kattwinkel 1993

Walti 1995

Bevilacqua 1996

Soll 2001

TYPICAL ESTIMATE

Kendig 1991

Randomized Controlled Trials, n=8

Number Of Enrolled Infants and Gestational Age, n=2816


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Prophylactic versus Rescue Treatment with Curosurf

Meta-Analysis of 3 Trials, n= 671*

* Egberts et al, Pediatrics 1997; ** Walti et al, Biol Neonate 2002

00 0.50.5 11 1.51.5 22

Odds RatioOdds Ratio

increased riskdecreased risk

Severe RDS

Mortality

CLD

ICH

total

severe

**


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Comparison of mortality after prophylactic and rescue

surfactant therapy in infant of


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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


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The Early versus late treatment trial (n=182)

Complications

* p < 0.05

Treatment Early Late

n=86 n=96

Intracerebral

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

Mortality 9,3 % 22,9 % *

Bevilacqua et al, J Perinat Med, 1993


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Collaborative European Multicenter Study Group

- Single versus multiple doses - (1988 - 1990)

Speer et al, Pediatrics 1992

omplications Single dose Multiple doses

n=176 n=167

neumothorax 18% 9%**

ortality 21% 13%*

urvival without BPD 67% 73%

*p < 0.05 ** < 0.01


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Curosurf 4 Trial

Up to 300 mg/kg Curosurf isas good as up to 600 mg/kg when

28 days outcome is assessed.

Halliday et al., Arch Dis Child, 1993


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0

0 0

5

10

15

20

20

40

60

80

100

Minutes

SaO%M

ABP,mmH

G

PaCO2

kPa

120

MABP

SaO2

PaCO2

S f S f


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sysBP(mm

Hg)

Segerer et al, Pediatr Res 1993 min after surfactant instillation

0 2 5 10 15 20 30 40 50 6020

40

60

80

100

120

140

Bolus (200 mg/kg, n=6)

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

Surfactant Bolus vs Slow Infusion in Rabbits

S f t t B l Sl I f i i R bbit


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PaO2(mmHg)

Segerer et al, Pediatr Res 1993

0 2 5 10 15 20 30 40 50 600

100

200

300

400

500

600

Bolus (200 mg/kg, n=6)

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

min after surfactant instillation

Surfactant Bolus vs Slow Infusion in Rabbits


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5 s

10 s

10 s 15 s

25 s

20 s

30 s 40 s 50 s

Curosurf instillation: first minute

Ingimarsson et al, Biol Neonate, 2000


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2 min 4 min 6 min

8 min

12 min 16 min 20 min 24 min

8 min

Curosurf instillation: 2 - 24 min


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

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

Bolus Dual-lumen instillation

Episodes of hypoxia 40% 18%

Efficacy +++ +++

Complications (+) (+)


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

Surfactant Therapy and Nasal CPAP*

1 dose of Curosurf (200mg/kg)

Preterm infants with

moderate RDS on nasal CPAP

Reduced need ofsubsequent mechanical ventilation


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Results of Meta-analysis of 5 trials

Relative Risk and 95% CIRelative Risk and 95% CI

UTCOME (# studies)UTCOME (# studies)

EarlyEarly

SurfactantSurfactantSelectiveSelective

SurfactantSurfactant

0.50.5 1.01.0 2.02.0 4.04.00.20.2

DecreasedDecreased IncreaseIncreaseRiskRisk

0.50.5 1.01.0 2.02.0 4.04.00.20.2

Airleak (4)Airleak (4) 4% 8%4% 8%

Mortality (3)Mortality (3)

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

Surfactant Use (5)Surfactant Use (5) 100% 63%100% 63%

Need for MVNeed for MV(5)(5)

37% 56%37% 56%

1% 3%1% 3%

INSURE

n=322 n=312

Cochrane Controlled Trial Register (2005)

Eff t f N t l S f t t


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Effects of Natural Surfactants

vs Colfosceril Palmitate(Exosurf)

7 randomized trials, 3756 preterm infants7 randomized trials, 3756 preterm infants

Air leaksAir leaks

MortalityMortality

00 11 22

Odds ratioOdds ratio

0.520.52

0.80.8

Halliday HL. Drugs. 1996;51:226237.

Favors syntheticFavors syntheticFavors naturalFavors natural

C i f P t t(Al ) d


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Ainsworth et al. Lancet. 2000;355:13871392.

Comparison of Pumactant(Alec) and

Poractant alfa(Curosurf) in Neonates

at 2529 Weeks Gestation

PumactantPumactant

(n=100)(n=100)

31%31%

Poractant alfaPoractant alfa

(n=99)(n=99)

14%*14%*

The trial was stopped earlyThe trial was stopped early

MortalityMortality

*P= 0.006


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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

1Bloom et al, Pediatrics 1997; 2Bloom et al, Pediatrics 2005; 3Bloom et al, Pediatrics 2005

Curosurf vs Survanta Rescue Trial


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Curosurf vs. Survanta Rescue Trial

Changes in FiO2

Speer et al, Arch Dis Child 1995

FiO2

0 1 2 3 4 5 6 7 8 9 100.20.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (days)

= Curosurf

= Survanta

*

**

p


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11.4 %12.5 %O2 at 36 wks PCA

12.5 %3 %IVH Gr. III-IV

35 %21.2 %IVH Total

12.5 %3 %Mortality

12.5 %6.1 %PTX

10 %3 %PIE

Survanta(n = 40)

Curosurf(n= 33)

Speer et al. Arch Dis Child 1995

No Difference in Death or BPD

Curosurf vs. Survanta Rescue Trial (3)


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Meta-Analysis Curosurf vs Survanta


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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 6/2620/302 (6,7%)

32/302(10,5%)

* 100 mg/kg Curosurf

OR 0.55 (0.31-0.98 CI)

Halliday, Biol Neonate 2005

CUROSURF vs SURVANTA


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CUROSURF vs. SURVANTA

Effect on Mortality

OutcomeRisk Difference

( 95% CI ) 0.5 1.0 2.0 4.00.2Decreased IncreasedRisk


0.5 1.0 2.0 4.00.2

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)

Halliday, Biol Neonate 2005

Surfactant Therapy Recommendations


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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


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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


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Natural surfactant preparations

acute none

chronic no sensitation against

apoproteins

no differences in neuro-

logical long-term outcome( treated / controls )

slow - virus infections ?

Adverse effects

Conclusions: Surfactant Therapy


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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


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Alexandria Egypt RDS 04-09