Surfactant Agents
I.
Definitions
a. Surfactant: A surface-active agent that lowers surface tension
i. Examples
1. soap
2. detergent
b. Surface Tension: Force caused by attraction between like
molecules that occurs at liquid-gas interfaces and that holds the
liquid surface intact
i. Units of Measure: dynes/centimeter (dyn/cm)
1. the force required to cause a 1 cm rupture in the
surface film
ii. a droplet forms because a liquid’s molecules are more
attracted to each other than the surrounding gas
c. LaPlace’s Law: Physical principle that describes and quantifies the
relationship between the internal pressure, amount of surface
tension and the radius of a drop or bubble
i. In the alveoli where there is a single air-liquid interface,
LaPlace’s Law is: Pressure=(2 x ST)/ r, where
1. ST = surface tension
2. r = radius of the alveoli
II.
Application to the Lung
a. Increased surface tension can cause collapse or difficulty opening
the alveoli
i. Surfactant lowers the surface tension to decrease the
pressure needed to open the alveoli
b. In pulmonary edema, the surface tension of the liquid allows the
formation of a bubbly froth
i. Lowering the surface tension will cause the foam bubbles to
collapse and liquefy
III.
Clinical Indications for Exogenous Surfactants
a. Prophylactic Treatment
i. Prevention of RDS in very-low-birth-weight infants and infants
with higher birth weights who have evidence of immature
lungs, at risk for developing RDS
b. Rescue Treatment
i. Retroactive or “rescue” treatment of infants who have
developed RDS
1. the basic problem in RDS is lack of pulmonary
surfactant as a result of lung immaturity
2. increased ventilating pressure is required to expand the
alveoli during inspiration, which will lead to respiratory
failure
IV.
Previous Surfactant Agents in Respiratory Care
a. Ethyl alcohol
i. Application
1. used for treating pulmonary edema
2. was given by nebulizer
a. 3 - 5 ml. of 30 - 50% solution
ii. Mode of Action
1. alcohol lowered the surface tension of the foamy
exudate, reducing it to a liquid, clearable state
iii. Disadvantages
1. efficacy not proven
2. toxic to membranes
3. better alternatives are available today
b. Mucus Wetting Agents (Detergents)
i. Examples
1. Alevaire
2. Tergamist
ii. Indication
1. to improve water penetration and facilitate transport
and expulsion of adhesive mucus
iii. Mode of Action
1. these agents may interact with mucus to produce
emulsification
a. The mucus will dissolve or disperse into smaller
molecules
iv. Efficacy
1. efficacy in vivo is not proven
c. Phospholipids
i. Coating of the airway epithelium by phospholipids may serve
as a lubricant for mucus transport
ii. May offer another alternative to normalizing mucociliary
transport and mucus clearing in disease states causing mucus
hypersecretion or decreased clearance of secretions
iii. There are no agents in general clinical use at this time
V.
Exogenous Surfactants
a. Exogenous
i. Originating outside the body
1. other humans
2. animals
3. laboratory synthesis
b. Clinical Use
i. to replace missing or immature surfactant in premature
infants
ii. investigated for use in adults with disease processes that
have low surfactant (ARDS)
c. History and Development of Exogenous Surfactants
Year Event
1929 Von Meergaard showed that lungs were more difficult to inflate
with air than with fluid
1956 Clements measured the surface tension of lung fluid extracts
1958 Dipalmitoylphosphatidylcholine (DPPC) is identified by
Clements and associates as the main surface-active
component of pulmonary surfactant
1959 Avery and Mead showed that surface tension is higher in the
lungs of infants with hyaline membrane disease than in the
lungs of normal infants
1964 Aerosols of synthetic DPPC are attempted in RDS, with little
success
1972 Enhorning and Robertson demonstrate the effectiveness of
surfactant replacement in premature animals
1980 Fujiwara and associates report success in exogenous
surfactant therapy in infants, using “lyophilized artificial
surfactant” (bovine extract, Surfactant TA)
1990 Colfosceril palmitate (Exosurf Neonatal, Burroughs Wellcome)
approved for general use
1991 Beractant (Survanta, Ross Laboratories) approved for general
use
1998 Calfactant (Infasurf, Forest Pharmaceuticals) approved for
general use
1999 Poractant alfa (Curosurf, Dey Labs) approved for general use
VI.
Composition of Surfactant
a. Lipids (85-90%)
i. Phospholipids (~90%)
1. Phosphatidylcholine
a. Dipalmitoylphosphatidylcholine (DPPC)
i. most prominent in reducing surface tension
2. phosphotidylglycerol
3. phosphatidylethanolamine
4. phosphatidylserine
5. phosphatidylinositol
6. spingomyelin
ii. Neutral Lipids (10%)
1. cholesterol and others
b. Proteins (10%)
i. Surfactant protein A (SP-A)
1. regulates secretion and reuptake of surfactant to Type
II cell
ii. Surfactant protein B (SP-B)
1. improves spreading of phospholipids in the alveolus
iii. Surfactant protein C (SP-C)
1. improves spreading of phospholipids in the alveolus
iv. Surfactant protein D (SP-D)
1. no clear role
VII.
Production and Regulation of Surfactant
a. Production
i. Synthesized in the type II alveolar cells
ii. Stored in vesicles called lamellar bodies
iii. Secreted by exocytosis into the alveolus
iv. The major stimulus for secretion is inflation of the lung
b. Regulation
i. Endocytosis back into the type II cell
1. most surfactant (90-95%) is taken back into the type II
cell, reprocessed, and resecreted
a. this is the reason that exogenously administered
surfactant is successful in replacing missing
surfactant with one or two doses
ii. Clearance/degradation by alveolar macrophages
VIII. Others Benefits of Surfactant
a. Contributes to host defense
i. Increased bacterial killing
ii. Modifies macrophage function
iii. Down-regulates the inflammatory response
1. decreases mediator release
iv. enhances ciliary beat frequency
IX.
Types of Exogenous Surfactant Preparations
Category
Natural
Description
Surfactant from
natural sources
(human or animal)
with addition or
removal of substances)
Examples
Survanta (bovine)
Surfactant TA (bovine
Curosurf (porcine)
Infasurf (bovine)
Alveofact (bovine)
Synthetic
Synthetic natural
X.
Surfactant that is
prepared by mixing in
vitro synthesized
substances that may
or may not be in
natural surfactant
Surfactant prepared in
vitro with genetic
engineering
Exosurf
ALEC
None at present
Specific Exogenous Surfactant Preparations
a. Colfosceril palmitate (Exosurf Neonatal)
i. Indications
1. Prophylactic therapy of infants weighing less than
1350g birth weight
2. Prophylactic therapy of infants with birth weights
greater than 1350g with evidence of pulmonary
immaturity and at risk for RDS
3. Rescue treatment of infants who have developed RDS
ii. Dosage
1. 5 ml/kg of the reconstituted suspension q12° X 2 - 3
doses
iii. Preparation
1. available as a dry powder that is reconstituted with 8 ml
sterile water prior to use
iv. Administration
1. instilled directly into the endotracheal tube through a
side port adapter attached to ET tube, in 2 divided
aliquots
a. 1st half of dose in midline position
i. infant rotated to the right and ventilated for
30 seconds
nd
b. 2 half of dose in midline position
i. Infant rotated to the left and ventilated for
30 seconds
2. a single vial can treat up to a 1600 g infant
a. 5 ml/kg x 1.6 kg = 8 ml
b. Beractant (Survanta)
i. Indications
1. Prophylactic therapy of premature infants less than
1250g birth weight or with evidence of surfactant
deficiency and risk of RDS
2. Rescue treatment of infants with evidence of RDS
ii. Dosage
1. 4 ml/kg (100 mg/kg) of the suspension q6°
iii. Preparation
1. available as a vial containing 8 ml of suspension with
200 mg active ingredient (25 mg/ml)
iv. Administration
1. instilled directly into the endotracheal tube through a 5French catheter, in 4 divided aliquots
2. the infant is placed in 4 different positions and manually
or mechanically ventilated for 30 seconds
3. a single vial can treat up to a 2000 g infant
a. 4 ml/kg x 2 kg = 8 ml
v. Handling
1. keep refrigerated
2. warm at room air for at least 20 minutes prior to
administration
3. unopened vial may be returned for refrigeration within 8
hours
4. used vials should be discarded
c. Calfactant (Infasurf)
i. Indications
1. The prevention of RDS in premature infants < 29 weeks
of gestational age at high risk for RDS
2. Rescue treatment of premature infants less than or
equal to 72 hours of age who develop RDS and require
endotracheal intubation
ii. Dosage
1. 3 mL/kg of the suspension q12 h up to 3 doses
iii. Preparation
1. available as a vial containing 6 ml of suspension with
210 mg of active ingredient
iv. Administration
1. Side-port adapter
a. The dose in given in two aliquots
i. Position the infant with either the right or
left side dependent
ii. Administer half the dose in small bursts to
coincide with the inspiratory cycle, over 20
to 30 breaths
iii. Reposition and administer the other half of
the dose in the opposite position
2. Catheter
a. The dose is given in four aliquots, with the
catheter removed between each instillation
b. Each portion is given with the infant in a different
position
i. Prone
ii. Supine
iii. Right lateral
iv. Left lateral
c. The infant is ventilated for 0.5 to 2 minutes
between portions
3. a single vial can treat up to a 2000 g infant
a. 3 ml/kg x 2 kg = 6 ml
d. Poractant alfa (Curosurf)
i. Indications
1. For the treatment or rescue of RDS in premature infants
2. Unlabeled Uses
a. Prophylaxis for RDS
b. ARDS resulting from viral pneumonia
c. HIV-infected infants with Pneumocystis carinii
pneumonia (PCP)
d. ARDS after near-drowning
ii. Dosage
1. 2.5 mL/kg
2. Repeat doses of 1.25 mL/kg birth weight q12h x 2
iii. Preparation
1. two preparations available
a. a vial containing 1.5 ml of suspension containing
120 mg of active ingredient
b. a vial containing 3.0 ml of suspension containing
240 mg of active ingredient
iv. Administration
1. instilled directly into the endotracheal tube through a 5French catheter
a. The dose is given in two aliquots
i. Each portion is given with the infant in a
different position
1. right side dependent
2. left side dependent
ii. The catheter is removed between portions
and the infant is manually ventilated with
100% O2 for 1 minute
2. a single 3.0 ml vial can treat up to a 1200 g infant
a. 2.5 ml/kg x 1.2 kg = 3 ml
XI.
Mode of Action
a. Exogenous surfactants replace and replenish a deficient
endogenous surfactant pool in neonatal RDS
i. Increased FRC
1. dramatic improvement in oxygenation
XII.
Hazards and Complications of Surfactant Therapy
a. During instillation
i. airway occlusion
1. relatively large volumes are instilled into the ETT
ii. desaturation
1. impaired diffusion
iii. bradycardia
1. heart rate < 100 bpm in a neonate
a. normally 120-160 bpm
2. caused by hypoxia and vagal stimulation
b. Post-instillation
i. high arterial oxygen (PaO2) values
1. wean O2 to maintain PaO2 50-70 torr
ii. over-ventilation and hypocarbia
1. decrease ventilating pressures as compliance improves
to prevent barotraumas
iii. apnea
1. irritation to the airway causes apnea in a neonate
iv. pulmonary hemorrhage
1. factors that increase risk
a. < 700 g birth weight
b. younger
c. male
d. patent ductus arteriosus (PDA)
XIII. Factors in Surfactant Selection
Parameter
Response time
Administration
Drug preparation
Side effects
Synthetic (Colfosceril)
Slower in onset (several
hours)
During mechanic ventilator
breath
Must reconstitute before
use
No proteins to stimulate
immune response; no
infectious agents present
Natural (Beractant)
Rapid in onset (5-30 min)
Removed from ventilator
Refrigerated suspension;
must warm prior to use
Proteins may elicit
immune response;
concern over sterilization
Cost
Similar
effectiveness
Similar
XIV. Benefits of Surfactant Therapy
a. Improved survival in RDS
b. Increased oxygenation
c. Decreased days of ventilatory support and supplemental O2