Surfactant therapy

SURFACTANT THERAPY

Historical back ground

John F kennedy (May 29, 1917 – November 22, 1963)

JFK and  Jacqueline Kennedy Onassis

Surfactant therapy

• Development of lung• Fluid mechanics-surface tension• Surfactant origin • Composition• Lung maturity asessment• Surfactants• administrations

Embryology of lung development

Stages of lung development

• Embryonic • Pseudogladular• Canalicular• Saccular• alveolar

Embryonic stage• 4-7weeks gestation• Appears as ventral bud off the esophagus

caudal to laryngotracheal sulcus.• Groove between lung bud and esophagus

deepens and the bud elongates and divides to form main stem branch .

• Lung bud differentiates to form trachea and bronchi.

Pseudogladular stage• 7-17 weeks of gestation• 15-20 generation of airway branching occurs• Ciliated cells,goblet cells and basal cells are

in proximal epithelium• Regulators of branching morphogenesis are

FGF-10,FGF-7,EGF,TGF alpha

Canalicular stage• 17-26weeks gestation• Transformation of previable lung to

viable lung• Formation respiratory bronchiole• By 20 weeks there is differentiation of

Type 1 pneumocytes-structural cell of alveolus

• Appearance of lamellar bodies in type 2 pneumocytes-site for surfactant storage

Saccular stage and alveolar stage• Saccular-27-36weeks• Alveolar->36weeks• Terminal sac is the respiratory bronchiole or

alveolar duct that is elongation ,branching and widening

• Alveolarization is initiated from terminal saccule by appearance of septa in associated with capillary ,elastin fibers and collagen fibers

• Alveolar number increases from about 32weeks gestation to term when human lung contains 50-150 million alveoli.

• Adult lung has 500 million alveoli.

Factors affecting alveolarization Factors that delay alveolarization• Mechanical ventilation • Antenatal and post natal steroids• Pro-inflammatory mediators• Poor nutrition• Hyperoxia/hypoxia• Chorioamnionitis

Factors that stimulate alveolarization• Vitamin A• thyroxin

Surface tensionElastic tendency of a fluid surface which makes it to acquire least surface area.

Contd….

Intermolecular attraction between water molecules,water molecules have both (+) and (-) charge.Opposite charge attract each other creating intermolecular attraction.

Law of laplace Surface tension to the enclosed pressure.

P=2T/r

SurfactantCompound which reduces surface tension when added to a liquid.Amphiphilic—has both hydrophopic and hydrophilic group

Pressure volume curves• Pressure needed to open a lung unit is related to the

radius of curvature and surface tension of the meniscus of fluid in the airspace leading to the lung unit.

• In collapsed lung or fluid filled lung,there are different units with different radii.

• Units with larger radii and lower ST pop open 1st because with partial expansion radius increases and force needed to finish opening the unit decreases.

• Movement of fluid with high surface tension in the airway causes very high sheer forces that can disrupt the alveolar epithelium.

• With surfactant treatment fluid menisci in the airways have lower ST that decreases the opening pressure from 25 cm H2O to 15 cm H2O.

surfactantOrigin

1)Alveolar type 2 cells • Compact cuboidal cells• Covers 2% of alveolar surface usually present at

corners of airspaces• Differentiate from columnar epithelium during

canalicular phase• Biosynthesis of surfactant occurs in endoplasmic

reticulum of type 2 cells • Phospholipids move via intracellular pathways

towards lamellar bodies.

Lamellar bodies• About 1.5 micrometre • Consists of limiting membrane surrounding about 20-

70 closed packed phospholipid bilayer.• These lamellar bodies contain –lipids ,surfactant

proteins A,B,C

Recycling of surfactant• Degraded locally in alveoli and small

airways.• Break down product adsorbed and

recycled by alveolar cells• >90% phophotidylcholine is reprocessed • Turnover time is 10hrs• Negative feedback regulation of

surfactant production mediated by SP-A binding to type 2 cells

• Surfactant secretion is controlled by :- a)stretch receptors b)stimulation of gas entering the lung c)alveolar distension

Composition of surfactant

Complex mixture of

phospholipids

Neutral lipids proteins

phospholipids• 70%-80%-phophatidyl choline 5%-10%phoohatidylgylcerol 10%phosphotidylinositol/phosphatidyl serine

• 60% of phophatidyl choline has both fatty acids saturated with the primary saturated fatty acid is palmittic acisDPPC

• Palmittic acid residue has non polar (hydrophobic) oriented towards air and polar (hydrophilic)oriented into the water surface.

Contd……Other lipids 10% is neutral lipids i.e cholesterol ,triglycerides,free fatty acids

Sphingomylin minor component of surfactant ,remains unchanged through gestation and thus change in amount of DPPC or lecithin can be assessed by comparing with amount of Sphingomylin.

Surfactant proteins

• 4 proteins -SP-A SP-B SP-C SP-D• 5-10% of surfactant

Surfactant protein A• Constitutes 5% ofsurfactant weight.• Located on human gene chromosome no

10• Present in lamellar bodies• Synthesis increased after 28weeks of

gestation • SpA binds to and confers calcium

dependent aggregation on surfactant proteins

• Roledetermines structure of tubular myelin and stability and rapidity of spreading and recycling of phospholipids.

• Prevents accumlation of surfactant

Surfactant protein B

• Contains highly positive charged amino acid residues positioned near phospholipid head groups at membrane surface.

• Located on chromosome 2• Detectable around 25weeks in type 2

cells. • Glucocorticoids increase expression of Sp-

B.• Stored in lamellar bodies ,secreted with

phospholipids.

Contd….• Required for spreading of surfactant on to

air water interface.• Protects films from inactivation by serum

proteins.• Absence of Sp-B is associated with marked

decrease or absence of phospholipids.• Autosomal recessive.• Def causeshypoxemic respiratory failure

within 1st of life refractory to mechanical ventilation,surfactant therapy,stroids and ECMO.

• Can present as congenital alveolar proteinosis.

Surfactant protein C• Small hydrophobic protein.• Expression occurs in type 2 cells • Gene –chromosome 8.• Imparts surface like properties to phopholipids.• Defassociated with ILD In finnish population assc.. With RDS and prematurity

Surfactant protein D• Produced by type 2 cells.• Does not have significant surfactant like

activity.• Steroid increased expression of Sp-D .

Factors affecting surfactant production1)Glucocorticoi

ds cortisols

Induces fetal lung fibroblast

Produce fibroblast pneumocyte factor

Stimulates surfactant production

2)Beta adrenergic drugsStimulate

adenylcyclase

Increase in cAMP

Inhibits phosphodiestera

se

Increased production of surfactant

3)Thyroid hormone• T4 increases surfactant production• But does not cross placenta.• But T3 given to pregnant ratsincreased T3

in fetus and increased type 2 cell production.

• TRH readily crosses placenta and increases surfactant.

4) Prolactin• Lower in infants with RDS and premature

babies• Male>female

5)Epidermal growth factor• Important in development of pulmonary epithelium• Infusion into lambs seen to prevent HMD• Mullerian inhibiting substances inhibits lung

maturation by blocking phosphorylation of EGF receptor

• Hence explains higher incidence of RDS in male.

6)Fibroblast pneumocyte factor• Glucocorticoids act on fetal lung fibroblasts to

induce production of FPF• Which stimulates synthesis of type 2 cells

7)Insulin• Inhibits Sp-A gene expression.• IDM have delayed appearance of

phosphotidyglycerols.

8)Intra uterine infections.• Chorioamnionitis • Bacterial endotoxins or IL-1 will induce lung

maturation.

9)Maternal addiction• Maternal narcotic addiction and smoking reduce

the incidence of RDS. • Heroin can mature the surfactantsynthesising

Assesment of surfactant maturation

1)lecithin/sphingomyelin ratio• Performed by thin layer chromatography• Risks of RDS is low if L/S >2

• ExceptionsIDM erythroblastosis fetalis IUGR meconium

2)TDx-FLM 2• Measures surfactant to albumin ratio• Uses fluroscent polarisation technology.• Value >55mg surfactant/g albumin

correlates FLM.

3)lamellar body count• Packages of phospholipids in type 2 cells.• Value >50,000 LB/micro L

4)Presence of phosphatidylglycerol • Appears late in lung maturation process• advnot affected by contamination with blood

and meconium.• Disadvlow sensitivity

5)Foam stability test• Formation of stable foam when amniotic

fluid is shaken with ethanol in test tube.

Role of antenatal steroids

• Reduces incidence and severity of RDS.• Induces enzymes for surfactant synthesis

and genes for production of surfactant proteins A,B,C& D.

• Dexamethasone stimulates Sp-B gene expression 2-3times adults levels in fetal lungs.

• Mature the non surfactant producing tissue of lung the septa become longer,thinner and less cellular with larger air spaces.

Timing • Considered in all women at risk of preterm

labour between 24-36weeks.• Benefit is maximal in babies delivered

between 24-168hrs after starting maternal therapy.

Courses:-

Betamethasone2doses(12mg ,IM),24hrs intervalDexamethasone4doses (6mg ,IM),12hrs interval

surfactant

Surfactant replacement Timing:

• prophylactic surfactant preparation delivered through ETT within minutes of birth.

• Rescue(selective) treatment-after the symptoms and signs of RDS present.

• early rescue(before 2hrs of age)

Response to surfactant therapy• Greater improvement in oxygenation and ventilation • Risk of PDA with LR shunt due to sudden fall in

pulmonary vascular resistance.• Decreased risk of pneumothorax.

Adverse reactionApnea,hypotension,pulmonary hemorrhage,endotracheal tube blocking and bradycardia

Procedure:• Position:-supine• under asceptic precautions• Infant should be suctioned before the procedure.• Ensure ETT at proper position i.e,1-2cms below the

vocal cords or 1-2 cms above the carina.• A sterile #5Fr feeding tube cut to the appropriate

length so that it reaches the tip of ETT• Infant is first disconnected from ventilator and

then feeding tube is inserted into ETT and 1st aliquot of surfactant is given over 2-3secs

• Infant is manually ventilated for 30secs suing pressure sufficient enough to achieve good chest expansion before returning the baby to ventilator.

Contd……..• If the infant remains on ventilator during dosing

raise the pressure by 1-2cm H2O• Allow approximately 1-2 minutes recovery time

after each aliquot.• Volume of surfactant will rise in ETT during

administration• If surfactant slow to subside,interrupt and hand

ventilate until ETT is cleared.• If surfactant fails to subside consider possibilty of

mucus plug.

Repeat doses:-• Neonates can receive up to 3 additional doses within

5days of life.• Criteria:- a)Positive response to previous dose. b)Increase in respiratory support. c)Atleast 10% FiO2 greater than FiO2 required after initial dose of surfactant.

preterm infant with RDS

>40%O2 needed<40% O2 needed

Wattch for apnea,severity odf distress ,CXR

Many episodes/downes >7/white out lung

Fewer or no apneic spells/downes 4-7,hazy lung fields

CPAP 7cm H2OFiO2 as needed

Continue CPAP

Assited ventilation and surfactant

INSURE surfactant therapy

Continue CPAP

Thank you