Drug Criteria & Outcomes: Exogenous Lung Surfactants in the Management of Neonatal Respiratory Distress Syndrome
By Monique Cannon, PharmD
Written as a PharmD candidate at Auburn
University School of Pharmacy, Auburn, AL
Surfactant preparations
- Beractant (Survanta) — natural bovine lung extract
- Calfactant (Infasurf) — natural surfactant from calf (bovine) lungs
Objectives
Evaluate and compare the efficacy, safety, and costs of the two most commonly used exogenous surfactants (beractant and calfactant) in respiratory distress syndrome (RDS).
- Select an exogenous surfactant to be used primarily in the Huntsville Hospital System in the prevention and treatment of RDS.
Surfactant compositions
Both beractant and calfactant use bovine lung as a source. They are similar in that they both contain phospholipids, neutral lipids, fatty acids, and hydophobic surfactant apoproteins. However, the proportions of the active ingredients are different.
Significant differences in constituents
Beractant: Lung tissue mince extract with a modified lipid profile.
Total protein: 1% of total phospholipids (wt/wt)
Surfactant apoprotein: C (SP-C) 99%
Surfactant apoprotein: B (SP-B) trace amounts, < 0.5%
Beractant contains phospholipids from lung cells as well as lung surfactant. It has higher levels of nonphosphatidylcholine, and these phospholipids limit the lowest surface tension attainable in bovine surfactant preparations.
The step in the beractant process that removes cholesterol likely removes the SP-B.
Calfactant: Extract of the surfactant lavaged from the alveolar spaces (contains the same lipid profile as natural surfactant).
Cholesterol: 5%
Total protein: ~2% of total phospholipids (wt/wt)
SP-C: 60%
SP-B: 40%
Indications
Both products are indicated for the prevention and treatment ("rescue") of RDS in premature infants.
Beractant:
Prophylaxis — In premature infants weighing less than 1,250 g or with evidence of surfactant deficiency. Give as soon as possible, preferably within 15 minutes of birth.
Treatment — In infants with RDS confirmed by X-ray and requiring mechanical ventilation. Give as soon as possible, preferably within 8 hours of birth.
Calfactant:
Prophylaxis — In premature infants younger than 29 weeks of gestational age and at significant risk for RDS. Administration should be as soon as possible, preferably within 30 minutes of birth.
Treatment — In infants younger than 72 hours of age with RDS (confirmed by clinical and radiologic findings) and requiring endotracheal intubation.
Mechanism of action
Endogenous lung surfactant is essential for effective ventilation because it modifies alveolar surface tension, stabilizing the alveoli. Lung surfactant deficiency is the cause of RDS in premature infants. Exogenous surfactants (calfactant and beractant) restore surface activity to the lungs of these infants by adsorbing to the surface of the air-liquid interface, modifying surface tension similarly to natural lung surfactant.
Dosage
Beractant
- 25 mg phospholipid/mL.
- 4 mL/kg of birth weight (100 mg of phospholipid/kg).
- Four doses can be administered in the first 48 hours of life.
- Doses should be given no more frequently than every six hours.
- The total calculated dose is divided into four quarter-doses (1 mL/kg aliquots), each given with the infant in a different position.
Calfactant
- 35 mg phospholipid/mL.
- 3 mL/kg of birth weight (105 mg of phospholipid/kg).
- Usually dosed every 12 hours for a total of up to three doses (as frequently as every six hours has been used for a total of four doses if the infant was still intubated and required at least 30% inspired oxygen to maintain a PaO2 < 80 torr).
- The total calculated dose is given in two aliquots of 1.5 mL/kg each, given with the infant in a different position.
Administration
Dosing procedures are the same between the products, with the exception of:
- The total beractant dose is divided into four aliquots; the total calfactant dose is divided into two aliquots.
- Calfactant does not require warming before administration.
The following applies to both products:
- For intratracheal adminstration only; these products should not be instilled into a mainstream bronchus.
- Store refrigerated (2-8°C).
- If settling occurs during storage, swirl the vial gently (do not shake) to redisperse.
- Date and time should be recorded on the vial whenever removed from the refrigerator.
- Unopened, unused vials that have been warmed to room temperature may be returned to the refrigerator within 24 hours of warming, and stored for future use.
- Surfactant preparations should not be removed from the refrigerator for more than 24 hours or warmed and returned to the refrigerator more than once.
- Vials are single-use and should be entered only once.
- Reconstitution or sonication is not required before use.
- Draw dose into a plastic syringe through a large-gauge needle (at least 20 gauge). Do not filter.
- Do not suction the infant for one hour after dosing unless signs of significant airway obstruction are present.
Beractant only
Before administration, beractant vials should be warmed by standing at room temperature for at least 20 minutes or hand warmed for at least 8 minutes. Artificial warming methods should not be used.
Overdosage
There have been no reports of overdosage with either product.
Beractant — Overdosage may result in acute airway obstruction. Treatment should be symptomatic and supportive.
Calfactant — Overdosage would result in overloading the lungs with an isotonic solution. Ventilation should be supported until clearance of the liquid.
Pharmacokinetics
Marked improvements in oxygenation may occur within minutes of administration (see Table 1). Therefore, frequent and careful clinical observation and monitoring of systemic oxygenation are essential to avoid hyperoxia. These values are not reported in the package insert, but are listed in a Drugdex drug evaluation from Micromedex that includes references.
Distribution
Endotracheal administration — surfactants are distributed uniformly to all lobes of the lung, distal airways, and alveolar spaces; gravitation to the dependent areas of the lung does not occur.
Surfactant concentrations are highest at the alveolar air-liquid surface, where it exists as a monolayer.
More even distribution is observed following prophylactic administration at birth as opposed to after birth when lung fluid rapidly decreases.
Metabolism
The metabolism of these products is not completely understood — it is thought to occur in the lungs, on the surface of alveoli or small airways.
Metabolism also may occur following uptake by alveolar type II pneumocytes.
Recycling may be a dominant pathway by which surfactant is taken up by type II pneumocytes and reused.
Contraindications
There are no known contraindications to calfactant and beractant therapy.
Precautions/warnings
Precautions and warnings are printed in the package inserts, but are not all representative of the comparative clinical trial of beractant vs. calfactant.
Both agents are for intratracheal use only.
Foreign proteins in bovine surfactants potentially can induce protein sensitization, and the risk of immunization may increase with retreatment. However, no cases of immunologic or allergic phenomena have been described.
Administration of exogenous surfactants often rapidly improves oxygenation and lung compliance. Therefore, patients should be carefully monitored so that oxygen therapy and ventilatory support can be modified in response to changes in respiratory status.
Transient episodes of reflux of surfactant into the endotracheal tube, cyanosis, bradycardia, or airway obstruction have occurred during the dosing procedures. These events require stopping administration and taking appropriate measures to alleviate the condition. After the patient is stable, dosing can proceed with appropriate monitoring.
Beractant
Rales and moist breath sounds may occur transiently after administration. Endotracheal suctioning or other remedial action is not necessary unless signs of airway obstruction are present.
Increased probability of post-treatment nosocomial sepsis in beractant-treated infants was observed in the controlled clinical trials. The increased risk of sepsis among beractant-treated infants was not associated with increased mortality. The causative organisms were similar in treated and control infants. There was no significant difference between groups in the rate of post-treatment infections other than sepsis.
Incidences of sepsis in the beractant vs. calfactant clinical trial were similar and not statistically significant.
Use in infants weighing less than 600 g or greater than 1,750 g at birth has not been evaluated in controlled trials.
No information is available on the effects of doses other than 100 mg phospholipids/kg, more than four doses, dosing more frequently than every six hours, or administration after 48 hours.
Calfactant
When repeat dosing was given in the calfactant vs. colfoseril palmitate (Exosurf) trial, transient episodes of cyanosis, bradycardia, reflux of surfactant in the endotrachial tube, and airway obstruction were observed more frequently among infants in the calfactant-treated group. Incidences of cyanosis, bradycardia, reflux of surfactant into the endotrachial tube, and airway obstruction in the beractant vs. calfactant clinical trial were similar and not statistically significant.
An increased proportion of patients with both intraventricular hemorrhage and periventricular leukomalacia was observed in calfactant-treated infants in the calfactant vs. colfoseril palmitate controlled trial. These observations were not associated with increased mortality. (These events were not reported in the beractant vs. calfactant clinical trial.)
Data from controlled trials on the efficacy of calfactant are limited to doses of approximately 100 mg phospholipid/kg body weight and up to a total of four doses.
Adverse effects
the percentages of adverse effects associated with the use of calfactant that are listed in the package insert are those that occurred in a trial comparing colfoseril palmitate and calfactant (see Table 2). In this trial, calfactant was administered in the same manner as colfoseril palmitate, causing over-treatment and a higher incidence of adverse effects.
Incidences of adverse effects between calfactant and beractant were similar and not statistically significant in the comparative clinical trial.
Hydrophobic apoproteins as constituents of exogenous surfactants
Background. The content of surfactant proteins SP-B and SP-C in exogenous surfactants is a distinguishing feature among these products. SP-B is believed to enhance the absorption of the major phospholipid, dipalmitoyl phosphatidlycholine (DPPC), to the air-liquid interface and promote film spreading. It also may contribute to metabolic behavior.
Study design. Biophysical properties and physiologic effects of three exogenous surfactants (calfactant, beractant, and colfoseril palmitate) were compared in excised lungs to determine the importance of the hydrophobic proteins SP-B and SP-C.
Discussion/conclusions. Results of this study show that hydrophobic surfactant apoproteins SP-B and SP-C are important components of exogenous surfactant preparations.
All three surfactants studied contain DPPC as a major constituent.
Significant evidence supports that DPPC (a rigid saturated phospholipid) is the component primarily responsible for lowering surface tension to the low levels of < 1 mN/m.
DPPC can lower surface tension to this extent only if it reaches the air-liquid interface and subsequently is compressed in a surface film.
Though DPPC adsorbs poorly on its own, the hydrophobic surfactant apoproteins have been shown to be highly effective in enhancing the adsorption process.
Study limitations/weaknesses. The calfactant formulation used was composed of 30 mg phospholipid/mL, but the available product formulation contains 35 mg phospholipid/mL.
Pressure-volume mechanics studies were done using excised, lavaged rat lungs. Therefore, the possibility of the positive interactions between the exogenous surfactants with endogenous surfactant (usually present in patients) cannot be determined.
Surfactant Protein-B supplementation improves in vivo function of a modified natural surfactant
Background. SP-B and SP-C are critical for surface adsorption and lowering surface tension. Evidence that demonstrates the significance of SP-B in surfactant includes: 1) antibodies to SP-B can cause severe respiratory failure and 2) a genetic deficiency of SP-B causes lethal respiratory failure in term infants. Can beractant be improved by adding surfactant proteins?
Study design. The effect of the addition of SP-B or SP-B and SP-C (SP-BC) to beractant was evaluated in 27-day gestation preterm rabbits. Calfactant and beractant (with and without positive end-expiratory pressure [PEEP]) also were compared.
- Measured parameters included:
- Ventilatory pressure requirements
- Expiratory time constants
- Dynamic compliance
- Pressure-volume curves
- Lung volume
Results. Results are reported in Table 3.
For all the measurements made with 3 cm H2O PEEP, the addition of 2% SP-B (Chl) or 3% SP-BC (Chl) enhanced the function of beractant to be equivalent to that of sheep surfactant.
Addition of 2% SP-B (H2O) did not improve dynamic compliance or the expiratory time constant at 15 min of ventilation, indicating that the method of addition (water or chloroform) of SP-B to beractant was important.
For all measurements made with 0 cm H2O PEEP, beractant + 2% SP-B (Chl) performed similarly to sheep surfactant and better than beractant alone or beractant + 0.5% SP-B (Chl).
On 0 cm H2O PEEP, calfactant performed better than beractant at all measured parameters (all with statistical significance, P < 0.05).
Discussion/conclusions. Addition of 2% SP-B (Chl) or 3% SP-BC (Chl) to beractant augments its short-term pf performance to be equivalent to that of sheep surfactant.
All indicators of function became essentially equivalent to those of sheep surfactant. Compliance improved with or without PEEP, expiratory time constants became longer, and pressure-volume curves were superimposable.
The results of this study are consistent with the critical role of SP-B in surfactant function.
Comparison of calfactant to beractant in RDS
Study design. Prospective, randomized, double-blind, multicenter clinical trial.
Treatment arm: infants weighing less than 2,000 g at birth (no minimum) and less than 48 hours of age; with radiographically confirmed RDS requiring endotracheal intubation; and with an FIO2 > 0.4, PaO2 < 80 torr, or an a/A oxygen ratio of < 0.22.
Prevention arm: infants that delivered before 30 weeks gestation and weighed less than 1,250 g at birth or were younger than 15 minutes old.
Administration, storage, and dispensing followed the beractant package insert. Both treatments were administered at the recommended dose for beractant of 100 mg/kg. A special 25 mg/mL concentration of calfactant was used to maintain masking.
Results. Results are summarized in Table 4 and Table 5. In the treatment arm, no significant differences were noted in the incidence of mortality, chronic lung disease, dosing related events, or complications of prematurity. In addition, infants receiving calfactant required significantly less oxygen and had significantly lower mean airway pressures within one hour of administration.
In the prevention arm, beractant infants required more days of intermittent mechanical ventilation and oxygen supplementation, primarily because of the survival of those weighing less than 600 g at birth. These events data from the prevention arm are skewed due to the unusually high survival rate of those babies weighing less than 600 g in the beractant group. There were no significant differences in the incidence of adverse events, survival to 36 weeks, postmenstrual age without the need for oxygen supplementation, or dosing complications.
Discussion/conclusions. The treatment arm showed that calfactant, when administered according to the beractant protocol, produced a greater initial improvement in respiratory status that was better sustained at every dose. This was evidenced by lower oxygen and mean airway pressure (MAP) and by longer intervals between doses. Also, there were fewer patients who required the full calfactant treatment course.
The prevention arm showed that beractant-treated infants had longer duration of mechanical ventilation and oxygen supplementation, most likely as a result of an unprecedented survival rate in those weighing more than 600 g.
The survival rate of this subset of beractant infants (13 out of 19, 74%) is probably not reproducible because all other published data report that a majority of infants weighing less than 600 g die, whether treated with surfactant or not.
Differences between surfactants in biophysical testing and animal models with virtual surfactant depletion are difficult to document in a clinical trial in which almost all patients have endogenous surfactant. It has been proposed that all surfactant drugs, in addition to their independent surfactant activity, interact with existing endogenous surfactant and may serve as substrate for improved endogenous production.
The effect of any surfactant is a combination of surfactant activity, its interaction with endogenous surfactant, and the time for adequate endogenous material to be secreted.
Study limitations/weaknesses. Study was funded by ONY, the manufacturer of calfactant. Because of the unprecedented survival of those babies weighing less than 600 g in the beractant-treated prevention arm, the results were skewed and therefore less applicable.
Potential medication error?
In the event that calfactant is chosen as the primary exogenous surfactant used in the Huntsville Hospital System, dosing errors could possibly occur with the change.
With the slight difference in dose, (calfactant dose = 3 mL/kg; beractant dose = 4 mL/kg) an infant weighing 1,400 g may receive a dose of 5.6 mL instead of 4.2 mL. This may not seem significant, but in premature infants this is substantial (33% over the correct dose). Due to the possibility of this error, educational efforts for those who will be dosing/administering calfactant are imperative.
Huntsville Hospital cost/usage
Over the past 12 months, Huntsville Hospital used 348 vials of beractant (146 x 4 mL vials, 202 x 8 mL vials), with total beractant costs of more than $120,000. The manufacturer of calfactant, however, provides an approximate one-month supply of the drug at no cost as a "trial supply." An additional 5% cost reduction is offered for calfactant if it replaces beractant as the neonatal surfactant formulary agent. With these cost reductions for calfactant, it is estimated that neonatal surfactant annual drug purchases would be reduced by approximately $17,000 at Huntsville Hospital.
In addition, as reported in the comparative clinical trial of beractant vs. calfactant, calfactant maintained a longer duration of action, creating longer intervals between doses and fewer patients requiring the full treatment course, meaning fewer calfactant doses were actually given. If these events hold true in actual clinical practice, it is speculated that medication costs may be decreased. However this cannot be predicted and will only be determined with actual calfactant use (possibly in a trial/pilot program with calfactant).
Recommendation
Based on the comparative safety, efficacy, and cost savings of using calfactant over beractant, it is recommended that the neonatologists consider the possibility of calfactant becoming the primary exogenous surfactant used in the prevention/ treatment of RDS in the Huntsville Hospital System. However, this recommendation is pending the availability of the 3 mL vial. In addition, it is advised that the neonatologists consider a trial/pilot of calfactant with the free-month supply to assure that the conversion to calfactant is best for the patients and hospital system. Use of the two products can be evaluated through the pilot program comparing usage and outcome issues. If a pilot program is implemented, the results will be reported back to the P&T committee.
Pilot program experience
After four months of experience with calfactant as the primary neonatal surfactant at Huntsville Hospital, neonatologists report similar efficacy and safety outcomes as with those observed with beractant. (See Table 6).
Resources
• Bloom B et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997; 100:31-38.
• Egan, Edmund. Personal communication. ONY. July 2001.
• Hall, Cindy. Personal communication. Pharmacy buyer. Huntsville Hospital System Pharmacy. July 2001.
• Hall S, et al. Importance of hydrophobic apoproteins as constituents of clinical exogenous surfactants. Am Rev Respir Dis 1992; 145:24-30.
• Infasurf. In: Patient Package Insert. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2001.
• Lung Surfactants. In: Hebel SK, publisher. Drug Facts and Comparisons. St. Louis: Facts and Comparisons; 2001: 692-697.
• Mizuno K, et al. Surfactant protein-B supplementation improves in vivo function of a modified natural surfactant. Pediatr Res 1995; 3:271-276.
• Survanta [monograph in electronic version]. Micromedex Healthcare Series. Englewood, CO: Micromedex Inc.; 2001
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content