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.
i.
In the alveoli where there is a single air-liquid interface,
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 |
Description |
Examples |
|
Natural |
Surfactant from natural sources
(human or animal) with addition or removal of substances) |
Survanta (bovine) Surfactant TA (bovine Curosurf (porcine) Infasurf (bovine) Alveofact (bovine) |
|
Synthetic |
Surfactant that is prepared by
mixing in vitro synthesized substances that may or may not be in natural
surfactant |
Exosurf ALEC |
|
Synthetic natural |
Surfactant prepared in vitro with
genetic engineering |
None at present |
X.
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
b.
2nd 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 5-French
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
5-French 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 |
Synthetic
(Colfosceril) |
Natural
(Beractant) |
|
Response time |
Slower in onset (several hours) |
Rapid in onset (5-30 min) |
|
Administration |
During mechanic ventilator breath |
Removed from ventilator |
|
Drug preparation |
Must reconstitute before use |
Refrigerated suspension; must warm
prior to use |
|
Side effects |
No proteins to stimulate immune
response; no infectious agents present |
Proteins may elicit immune
response; concern over sterilization effectiveness |
|
Cost |
Similar |
Similar |
XIV.
Benefits of Surfactant Therapy
a.
Improved survival in RDS
b.
Increased oxygenation
c.
Decreased days of ventilatory support and supplemental O2