Pharmacologic Therapies I: Surfactant Therapy




The development of exogenous surfactant therapy in the early 1990s was a historic advance in neonatology that led to significant reductions in neonatal mortality. Exogenous surfactant therapy is now routinely used in the management of respiratory distress syndrome (RDS) in preterm infants and increasingly in other neonatal respiratory disorders such as meconium aspiration syndrome (MAS). This chapter provides an evidence-based overview of the use of exogenous surfactant therapy in neonatal respiratory disorders.


History


The development of effective surfactant preparations was the culmination of a series of investigations by pioneers of surfactant research, who described the existence and composition of surfactant, the role of surfactant in lowering surface tension, and the role of surfactant in maintaining alveolar stability. A landmark in our understanding of RDS was the demonstration of surfactant deficiency in the lungs of infants dying of extreme prematurity or hyaline membrane disease. Although the introduction of surface-active substances into the lung was suggested as early as 1947, the initial attempts to provide exogenous surfactant therapy for immature lungs were unsuccessful. These were followed several years later by successful attempts in animals and then in human neonates. After these initial efforts, numerous animal experiments and human clinical trials were conducted to study the efficacy of surfactant therapy, the relative efficacies of different surfactant preparations, the optimal timing of administration, the optimal dosage, and other aspects of exogenous surfactant therapy. The history and evolution of surfactant therapy have been reviewed in detail by several authors.




Surfactant Function, Composition, and Metabolism


The function, composition, secretion, and metabolism of mammalian surfactant have been reviewed by several authors and are summarized below.


Function


Pulmonary alveoli, where gas exchange occurs, are bubble-shaped and have a high degree of curvature. The surface tension of the moist inner surface is due to the attraction between the molecules in the alveolar fluid and tends to make the alveoli contract. Unchecked, this tendency would result in lung collapse. Surfactant greatly reduces the surface tension on the inner surface of the alveoli, thus preventing the alveoli from collapsing during expiration.


Composition


An accurate determination of the composition of pulmonary surfactant is difficult. To obtain surfactant for analysis, one must either wash out lungs (with the possible limitation of leaving important components behind) or extract surfactant from minced lungs (with the possible problem of adding cellular contaminants). Mammalian surfactant obtained by lung lavage consists of 80% phospholipids, 8% neutral lipids, and 12% protein. The predominant class of phospholipid (nearly 60%) is dipalmitoyl phosphatidylcholine (DPPC), with lesser amounts of unsaturated phosphatidylcholine compounds (25%), phosphatidylglycerol (15%), and phosphatidylinositol. Of all the constituents of surfactant, DPPC alone has the appropriate properties to reduce alveolar surface tension. However, DPPC alone is a poor surfactant because it adsorbs very slowly to air–liquid interfaces. Surfactant proteins or other lipids facilitate its adsorption.


Approximately half the protein in surfactant consists of contaminating protein from the plasma or lung tissue. The remaining proteins include four unique surfactant-associated apoproteins: SP-A, SP-B, SP-C, and SP-D. SP-A and SP-D are hydrophilic proteins and belong to a subgroup of mammalian lectins called collectins . They may play important roles in the defense against inhaled pathogens, and SP-A may have a regulatory function in the formation of the monolayer that lowers the surface tension. SP-B and SP-C are hydrophobic proteins and are required to enhance spreading of phospholipid in the airspaces. SP-B promotes phospholipid adsorption and induces the insertion of phospholipids into the monolayer, thus enhancing the formation of a stable surface film. SP-C enhances phospholipid adsorption, stimulates the insertion of phospholipids out of the subphase into the air–liquid interface, and may increase the resistance of surfactant to inhibition by serum proteins or by edema fluid.


Secretion and Metabolism


Surfactant is produced in the type II cells of the alveoli ( Fig. 31-1 ). It is assembled and stored in the lamellar bodies, which consist of concentric or parallel lamellae, predominantly composed of phospholipid bilayers. Lamellar bodies are extruded into the fluid layer lining the alveoli by exocytosis and form structures known as tubular myelin . Tubular myelin consists of long stacked tubes composed mainly of phospholipid bilayers, the corners of which appear fused, resulting in a lattice-like appearance on cross section. Tubular myelin is thought to be the major source of the monolayer surface film lining the air–liquid interface in the alveoli, in which the hydrophobic fatty acyl groups of the phospholipids extend into the air, whereas the hydrophilic polar head groups bind water. This surfactant monolayer lowers the surface tension at the air–liquid interface by replacing water at the surface. The phospholipid from the monolayer eventually reenters the type II cells through endocytosis and forms multivesicular bodies. These multivesicular bodies are either “recycled” by rapid incorporation into the lamellar bodies or degraded in lysosomes. Of note, all critical components of surfactant (DPPC, phosphatidylglycerol, SP-A, SP-B, and SP-C) are recycled.




FIG 31-1


Metabolism of surfactant. Solid line , surfactant + liquid; dashed and dotted line , SP-A; dashed line , SP-B, SP-C.

(From Jobe AH, Ikegami M. Clin Perinatol . 28:655, 2001.)




Types of Surfactant


Three types of exogenous surfactant are available: (1) surfactant derived from animal sources, (2) synthetic surfactant without protein components, and (3) synthetic surfactant with protein components.


Animal-Derived Surfactants


Current commercially made animal-derived surfactants are obtained from either bovine or porcine lungs. Beractant (Survanta) and surfactant TA (Surfacten) are lipid extracts of bovine lung mince with added DPPC, tripalmitoylglycerol, and palmitic acid. Calf lung surfactant extract (calfactant, Infasurf), SF-RI 1 (Alveofact), and bovine lipid extract surfactant (BLES) are bovine lung washes subjected to chloroform–methanol extraction. Poractant (Curosurf) is a porcine lung mince that has been subjected to chloroform–methanol extraction and further purified by liquid–gel chromatography. It consists of approximately 99% polar lipids (mainly phospholipids) and 1% hydrophobic, low-molecular-weight proteins (SP-B and SP-C). All the animal-derived surfactants contain SP-B and SP-C, but the lung mince extracts (Survanta and Curosurf) contain less than 10% of the SP-B that is found in the lung-wash extracts (Infasurf, Alveofact, and BLES). The purification procedure including extraction with organic solvents removes the hydrophilic proteins SP-A and SP-D, leaving a material containing only lipids and small amounts of hydrophobic proteins. Poractant, which is further purified by liquid–gel chromatography, contains only polar lipids and about 1% hydrophobic proteins (SP-B and SP-C in an approximate molar ratio of 1:2). None of the commercial preparations contain SP-A. A surfactant obtained from human amniotic fluid was originally tested in clinical trials but is not used as of this writing.


Synthetic Surfactants without Protein Components


The original exogenous products tested in the 1960s were synthetic surfactants composed solely of DPPC, which by itself cannot perform all the functions required of pulmonary surfactant. Current synthetic surfactants without protein are mixtures of a variety of surface-active phospholipids (principally DPPC) and spreading agents to facilitate surface adsorption. These products include Exosurf and ALEC (artificial lung-expanding compound). Colfosceril palmitate, hexadecanol, tyloxapol (Exosurf) consists of 85% DPPC, 9% hexadecanol, and 6% tyloxapol (a spreading agent). ALEC (pumactant), which is no longer manufactured, was a 7:3 mixture of DPPC and phosphatidylglycerol. These synthetic surfactants lack many of the components of animal-derived surfactant, particularly the hydrophobic surfactant proteins B and C.


Protein-Containing Synthetic Surfactants


The protein-containing synthetic surfactants contain synthetic phospholipids and proteins produced through peptide synthesis and recombinant technology that function similar to the hydrophobic proteins (SP-B and SP-C) of native human surfactant. Research is in progress to develop component protein analogues of the hydrophilic proteins SP-A and SP-D as well.


Of the surfactants containing SP-B analogues, the best studied is lucinactant (Surfaxin), which contains a mimic of SP-B called sinapultide or KL4 peptide . KL4 is a 21-residue peptide consisting of repeated units of four hydrophobic leucine (L) residues, bound by basic polar lysine (K) residues arranged in the following order: KLLLLKLLLLKLLLLKLLLLK. This structure mimics the repeating pattern of hydrophobic and hydrophilic residues in the C-terminal part of SP-B and stabilizes the phospholipid layer by interactions with the lipid heads and the acyl chains. In lucinactant, sinapultide is combined with DPPC, palmitoyl-oleoyl-phosphatidylglycerol, and palmitic acid. Other synthetic surfactants containing SP-B and SP-C analogues have also been tested in animal studies.


Of the surfactants containing SP-C analogues, recombinant SP-C (rSP-C) surfactant or lusupultide (Venticute) has been studied in vitro and in animals and has shown efficacy. It contains rSP-C combined with DPPC, palmitoyloleoylphosphatidylglycerol, palmitic acid, and calcium chloride. rSP-C is similar to the 34-amino-acid human SP-C sequence, except that it contains cysteine (in place of phenylalanine) in positions 4 and 5 and contains isoleucine (instead of methionine) in position 32.




Acute Pulmonary and Cardiac Effects of Surfactant Therapy


Immediate Pulmonary Effects of Surfactant Therapy


In animal models of RDS, administration of exogenous surfactant results in improved lung function ( Fig. 31-2 ) and improved alveolar expansion ( Fig. 31-3 ). Several studies in human neonates have shown that the administration of exogenous surfactant therapy leads to rapid improvement in oxygenation and a decrease in the degree of support provided by mechanical ventilation ( Fig. 31-4 ). These rapid changes are accompanied by an increase in the functional residual capacity and are followed by a slower and variable increase in lung compliance. A decrease in pulmonary ventilation–perfusion mismatch has also been reported.




FIG 31-2


Pressure–volume characteristics of lungs from 10 matched prematurely delivered rabbits after treatment with saline ( NaCl ), Exosurf ( EXO ), or surface-active material obtained by lavaging lungs of young adult rabbits with saline ( SAM ), plus ventilation for 30 minutes. Measurements were made 10 minutes after the animals died and their lungs were allowed to degas spontaneously.

(From Tooley WH, Clements JA, Muramatsu K, et al. Am Rev Respir Dis . 136:651, 1987.)



FIG 31-3


Expansion patterns in lung sections from premature rabbits. A, Well-expanded area in surfactant-treated fetus. The rounded appearance of the aerated alveoli contrasts with the pattern in B and with the wedge of unexpanded parenchyma (lower left). B, “Unexpanded” lung in control fetus that did not receive surfactant. The configuration of the alveoli reflects the fluid-filled state. Note abundant interstitial fluid around a pulmonary vein ( arrow ) (hematoxylin and eosin, original magnification ×27).

(From Robertson B, Enhorning G. Lab Invest . 31:54, 1974.)



FIG 31-4


Oxygenation measurements in Curosurf-treated and control infants at various intervals after randomization. Results are mean values and 95% confidence intervals. If confidence intervals are overlapping, bars are shown on only one side of the data point. Note that the time scale is not linear. Conversion factor: 1 kPa = 7.52 mm Hg. ∗ p < 0.05; ∗∗ p < 0.01; ∗∗∗ p < 0.001. A, Partial pressure of oxygen; B, Fraction of inspired oxygen; C, Ratio of partial pressure of oxygen to fraction of inspired oxygen; D, Arterio-alveolar oxygen ratio.

(From Collaborative European Multicenter Study Group. Pediatrics . 82:683, 1988.)


Immediate Effects on Pulmonary Circulation


The effect of surfactant treatment on the pulmonary circulation is unclear. In three studies pulmonary blood flow was unchanged with surfactant therapy. In contrast, others have reported a decrease in pulmonary artery pressure or an increase in pulmonary artery flow with surfactant therapy, as well as an increase in the ductal flow velocity from the systemic to the pulmonary circuit. It is uncertain whether these changes in pulmonary circulation are related to ventilation practices, blood gas status, or the surfactant treatment itself.


Radiographic Changes


In addition to these physiologic changes, treatment with exogenous surfactant also results in radiologic improvement, with chest radiographs after treatment often (but not always) showing a decrease in the signs of RDS. This clearing of the lungs can be uniform, patchy, or asymmetric, sometimes with disproportionate improvement of radiologic changes in the right lung.




Clinical Trials of Surfactant Therapy


Surfactant therapy is one of the best-studied interventions in neonatology and has been subjected to numerous randomized controlled trials comparing various treatment strategies. The findings from these trials, many of which are included in multiple systematic reviews in the Cochrane Database of Systematic Reviews, are summarized in the following sections. The results of meta-analyses are presented as the “typical” or “pooled” estimates of relative risk (RR) and absolute risk difference (ARD), with 95% confidence intervals (CI).


Surfactant Therapy Compared to Placebo or No Therapy


Many of the early trials in the late 1980s and early 1990s studied the effects of surfactant therapy compared to placebo or no therapy. Some of these trials studied the effects of prophylactic administration of surfactant to preterm infants at risk for developing RDS (prophylactic or prevention trials). Others studied the effects of treatment with surfactant in preterm infants with clinical and/or radiologic features of RDS (rescue or treatment trials). Some of these studies used animal-derived surfactant and others used synthetic surfactant. Systematic reviews of these trials show that, compared to placebo or no therapy, surfactant treatment or prophylaxis (with either animal-derived or synthetic surfactant) decreases the risk of pneumothorax and of mortality. Estimates from the meta-analyses indicate that there is a 30% to 65% relative reduction in the risk of pneumothorax and up to a 40% relative reduction in the risk of mortality. There were no consistent effects on other clinical outcomes such as chronic lung disease, patent ductus arteriosus, and intraventricular hemorrhage.


Further evidence of the benefits of surfactant therapy is derived from studies demonstrating decreased mortality and morbidity in very low birth-weight infants after the introduction of surfactant therapy into practice.


Prophylactic Surfactant Administration Compared to Postbirth Stabilization on Continuous Positive Airway Pressure and Selective Surfactant Administration


The rationale for prophylactic administration of surfactant is provided by the observation that in animal studies a more uniform and homogeneous distribution of surfactant is achieved when it is administered into a fluid-filled lung and by the belief that administration of surfactant into a previously unventilated or minimally ventilated lung will diminish acute lung injury. Even brief (15 to 30 minutes) periods of mechanical ventilation prior to surfactant administration have been shown, in animal models, to cause acute lung injury resulting in alveolar-capillary damage, leakage of proteinaceous fluid into the alveolar space, and release of inflammatory mediators, and to decrease the subsequent response to surfactant replacement. Surfactant-deficient animals who receive assisted ventilation develop necrosis and desquamation of the bronchiolar epithelium as early as 5 minutes after onset of ventilation. Prophylactic surfactant has been administered after intubating the infant immediately after birth (“before the first breath”). However, administration after initial resuscitation and confirmation of endotracheal tube position was found in a randomized trial to be equivalent or superior to immediate administration.


A systematic review included 11 randomized controlled trials that compared prophylactic surfactant administration to selective surfactant treatment, i.e., treatment of established RDS. All these trials used animal-derived surfactant. The selective treatment group had two categories of infants—those who were routinely stabilized on nasal CPAP immediately after birth and received surfactant if CPAP “failed” (more recent, larger studies with a high rate of maternal antenatal steroid administration) and those who were not stabilized on CPAP and received surfactant treatment at anywhere from 1.5 to 7.4 hours of age (older studies with a low rate of maternal steroid administration). Meta-analysis of studies without routine application of CPAP in controls demonstrated benefits with the use of prophylactic surfactant—a decrease in the risk of air leak and neonatal mortality. However, the analyses of studies that allowed for routine stabilization on CPAP demonstrated a decrease in the risk of chronic lung disease or death in infants stabilized on CPAP. When all studies were evaluated together, no benefits of prophylactic surfactant could be demonstrated. Furthermore, infants receiving prophylactic surfactant had a higher incidence of bronchopulmonary dysplasia (BPD) or death than did infants stabilized on CPAP (RR 1.12; 95% CI 1.02–1.24). Therefore in extremely preterm infants, the early use of CPAP with subsequent selective surfactant administration is the preferred management immediately after birth. Infants managed with CPAP should be monitored closely after birth, and those who show evidence of progressive respiratory failure from RDS should be intubated and given surfactant treatment early without delay. Administration of surfactant should preferably be followed by rapid extubation, and prolonged ventilation should be avoided.


In preterm infants who do not receive prophylaxis, early surfactant treatment of those with signs and symptoms of RDS is preferred. Six randomized controlled trials, including the largest randomized trial conducted in neonatology (the OSIRIS trial), have evaluated early versus delayed selective surfactant administration. The results of these trials are summarized in a systematic review. Of note, this is a comparison of what to do once an infant is intubated and not a decision about when to intubate for surfactant treatment. In these trials, early administration of surfactant consisted of administration of the first dose within the first 30 minutes to 2 hours of life. Two of the trials utilized synthetic surfactant (Exosurf Neonatal) and four utilized animal-derived surfactant preparations. The meta-analyses demonstrate significant benefits to early treatment of intubated infants with RDS: reductions in the risk of neonatal mortality (typical RR 0.84, 95% CI 0.74 to 0.95; typical risk difference [RD] −0.04, 95% CI −0.06 to −0.01)å, chronic lung disease (typical RR 0.69, 95% CI 0.55-0.86; typical RD −0.04, 95% CI −0.06 to −0.01), and chronic lung disease or death at 36 weeks (typical RR 0.83, 95% CI 0.75-0.91; typical RD −0.06, 95% CI −0.09 to −0.03). Intubated infants randomized to early selective surfactant administration also demonstrated a decreased risk of acute lung injury including a decreased risk of pneumothorax (typical RR 0.69, 95% CI 0.59-0.82; typical RD −0.05, 95% CI −0.08 to −0.03), pulmonary interstitial emphysema (typical RR 0.60, 95% CI 0.41-0.89; typical RD −0.06, 95% CI −0.10 to −0.02), and overall air-leak syndromes (typical RR 0.61, 95% CI 0.48-0.78; typical RD −0.18, 95% CI −0.26 to −0.09). A trend toward risk reduction for BPD or death at 28 days was also evident (typical RR 0.94, 95% CI 0.88-1.00; typical RD −0.04, 95% CI −0.07 to −0.00). No differences in other complications of RDS or prematurity were noted. Therefore preterm infants who do not receive prophylactic surfactant and exhibit the signs and symptoms of RDS should receive the first dose of surfactant as early as possible. Outborn infants are at highest risk of delayed administration. Tertiary referral units accepting outborn infants should attempt to develop systems to ensure that surfactant is administered as early as possible to these infants, either by the transporting team or, if appropriate, by the referring hospital. In inborn infants, delays in administration of surfactant occur if other admission procedures such as line placement, radiographs, and nursing procedures are allowed to take precedence over surfactant dosing soon after birth. Surfactant administration should be given priority over other admission procedures.


Early Surfactant Administration Followed Immediately by Extubation to Nasal Continuous Positive Airway Pressure


When surfactant therapy was first used, infants were maintained on mechanical ventilation after surfactant administration, ventilator support was gradually weaned as the pulmonary status improved, and the infant was extubated from low ventilator settings. This approach has been compared to a strategy of surfactant administration followed immediately (within 1 hour) by extubation to nasal CPAP (NCPAP) to prevent ventilator-induced lung injury (VILI) that can result from even brief periods of mechanical ventilation. This approach has been called the INSURE technique ( in tubate, sur factant, e xtubate to CPAP). Six randomized trials, all of which were trials of rescue surfactant administration, have compared the INSURE approach in spontaneously breathing infants with signs of RDS to later, selective administration of surfactant in infants with respiratory insufficiency related to RDS, followed by continued mechanical ventilation and extubation from low respiratory support. These trials are summarized in a systematic review. Most of these studies included infants with a gestation of 35 weeks or less and a birth weight of 2500 g or less. The meta-analysis in this review showed that compared to the traditional management strategy of gradual weaning, the INSURE approach reduced the need for mechanical ventilation (typical RR 0.67, 95% CI 0.57-0.79), air-leak syndromes (typical RR 0.52, 95% CI 0.28-0.96), and BPD (oxygen at 28 days, typical RR 0.51, 95% CI 0.26-0.99). A lower threshold for treatment at study entry (FiO 2 less than 0.45) resulted in a lower incidence of air leak (typical RR 0.46, 95% CI 0.23-0.93) and BPD (typical RR 0.43, 95% CI 0.20-0.92). A higher treatment threshold (FiO 2 greater than 0.45) at study entry was associated with a higher incidence of patent ductus arteriosus requiring treatment (typical RR 2.15, 95% CI 1.09-4.13). Since this systematic review two large randomized controlled trials were published. In a randomized trial by the Colombian Neonatal Research Network, 279 infants of 27 to 31 weeks’ gestation with RDS who were randomly assigned within the first hour of life to intubation, very early surfactant, extubation, and NCPAP required less ventilation and had a lower incidence of mortality and air leaks (pneumothorax and pulmonary interstitial emphysema) than infants assigned to nasal continuous airway pressure alone. In a large trial utilizing the INSURE technique the Vermont Oxford Network randomized 648 infants to prophylactic surfactant followed by a period of mechanical ventilation (PS), prophylactic surfactant with rapid extubation to bubble NCPAP (ISX), or initial management with bubble NCPAP and selective surfactant treatment (NCPAP). Compared with the PS group, the RR of BPD or death was 0.78 (95% CI 0.59-1.03) for the ISX group and 0.83 (95% CI 0.64-1.09) for the NCPAP group. There were no statistically significant differences in mortality or other complications of prematurity. In the NCPAP group, 48% were managed without intubation and ventilation, and 54% without surfactant treatment. These data suggest that spontaneously breathing preterm infants who show early signs of RDS should be given surfactant at a low threshold, after which they can be quickly extubated and placed on NCPAP to reduce VILI.


Targeted Surfactant Therapy


Several studies have addressed the use of rapid bedside tests such as the click test, lamellar body count, or stable microbubble test on a tracheal aspirate or a gastric aspirate specimen. Such tests can potentially supplement the use of clinical criteria in selecting preterm infants whose likelihood of RDS is high enough to merit surfactant therapy and perhaps avoid needless intubations and, in those already intubated, needless surfactant therapy. However, it is unclear whether the logistic challenges of performing these tests are worth the additional refinements in decision making.


Single versus Multiple Surfactant Doses


Many of the initial trials of surfactant therapy tested a single dose of surfactant. However, surfactant may become rapidly metabolized, and functional inactivation of surfactant can result from the action of soluble proteins and other factors in the small airways and alveoli. The ability to administer repeat or subsequent doses of surfactant is thought to be useful in overcoming such inactivation. The results of two randomized controlled trials that compared multiple dosing regimens to single-dose regimens of animal-derived surfactant extract for treatment of established RDS have been evaluated in a systematic review. In one study, after the initial dose of BLES, infants assigned to the multiple-dose group could receive up to three additional doses of surfactant during the first 72 hours of life if they had a respiratory deterioration, provided they had shown a positive response to the first dose and a pneumothorax had been eliminated as the cause of the respiratory deterioration. In the other study, infants in the multiple-dose group received additional doses of poractant at 12 and 24 hours after the initial dose if they still needed supplemental oxygen and mechanical ventilation. Approximately 70% of the infants randomized to the multiple-dose regimen received multiple doses.


The meta-analysis supports a decreased risk of pneumothorax associated with multiple-dose surfactant therapy (typical RR 0.51, 95% CI 0.30-0.88; typical ARD 0.09, 95% CI 0.15-0.02). There was also a trend toward decreased mortality (typical RR 0.63, 95% CI 0.39-1.02; typical ARD 0.07, 95% CI 0.14-0.00). No differences were detected in other clinical outcomes. No complications associated with multiple-dose treatment were reported in these trials. In a third study, in which synthetic surfactant was used in a prophylactic manner, the use of two doses of surfactant in addition to the prophylactic dose led to a decrease in mortality, respiratory support, necrotizing enterocolitis, and other outcomes compared to a single prophylactic dose. In the OSIRIS trial, which used synthetic surfactant, a two-dose treatment schedule was found to be equivalent to a treatment schedule permitting up to four doses of surfactant.


Criteria for Repeat Doses of Surfactant


The use of a higher threshold for re-treatment with surfactant appears to be as effective as a low threshold and can result in significant savings in costs of the drug. The criteria for administration of repeat doses of surfactant have been investigated in two studies, both of which used animal-derived surfactant. In one study the re-treatment criteria compared were an increase in the fraction of inspired oxygen by 0.1 over the lowest baseline value (standard re-treatment) versus a sustained increase of just 0.01 (liberal re-treatment). There were no differences in complications of prematurity or duration of respiratory support. However, short-term benefits in oxygen requirement and degree of ventilator support were noted in the liberal re-treatment group.


In another study, re-treatment at a low threshold (FiO 2 greater than 30%, still requiring endotracheal intubation) was compared to re-treatment at a high threshold (FiO 2 greater than 40%, mean airway pressure greater than 7 cm H 2 O). Again, there were minor short-term benefits to using a low threshold with no differences in major clinical outcomes. However, in a subgroup of infants with RDS complicated by perinatal compromise or infection, infants in the high-threshold group had a trend toward higher mortality than the low-threshold group. Based on current evidence, it appears appropriate to use persistent or worsening signs of RDS as criteria for re-treatment with surfactant. A low threshold for repeat dosing should be used for infants with RDS who have perinatal depression or infection.




Methods of Administration of Surfactant


A theoretical model for the transport of exogenous surfactant through the airways has been proposed, consisting of four distinct mechanisms: (1) the instilled bolus may create a liquid plug that occludes the large airways but is forced peripherally during mechanical ventilation; (2) the bolus creates a deposited film on the airway walls, either from the liquid plug transport or from direct coating, that drains under the influence of gravity through the first few airway generations; (3) in smaller airways, surfactant species form a surface layer that spreads because of surface-tension gradients, that is, Marangoni flows; and (4) the surfactant finally reaches the alveolar compartment where it is cleared according to first-order kinetics.


Administration through Catheter, Side Port, or Suction Valve


According to the manufacturers’ recommendations, beractant and poractant should be administered through a catheter inserted into the endotracheal tube; colfosceril should be administered through a side-port adapter attached to the endotracheal tube, and calf lung surfactant extract can be administered either through a catheter or through a side-port adapter. Other methods of administration of surfactant have been tested in randomized trials. In one randomized trial, the administration of beractant through a catheter inserted through a neonatal suction valve without detachment of the neonate from the ventilator was compared to the administration of the dose (with detachment from the ventilator) in two aliquots through a catheter and to the standard technique of administration of the dose in four aliquots through a catheter. Administration through the suction valve led to less dosing-related oxygen desaturation but more reflux of beractant than the two-aliquot catheter technique. In another study, the administration of poractant as a bolus was compared in a randomized trial to administration via a catheter introduced through a side hole in the tracheal tube adaptor without changing the infant’s position or interrupting ventilation. The numbers of episodes of hypoxia and/or bradycardia, as well as other outcomes, were similar in both groups. A slight and transient increase in PaCO 2 was observed in the side-hole group.


Administration through Dual-Lumen Endotracheal Tube


The administration of poractant through a dual-lumen endotracheal tube without a change in position or interruption of mechanical ventilation was compared to bolus instillation in a randomized trial. The dual-lumen group had fewer episodes of dosing-related hypoxia, a smaller decrease in heart rate and oxygen saturation, and a shorter total time in increased supplemental oxygen than the bolus group. The dual-lumen method has also been compared to the side-port method of administration of colfosceril in a randomized trial. No difference was found between the two methods in dosing-related hypoxemia.


Administration through a Laryngeal Mask Airway


Surfactant administration through a laryngeal mask airway (LMA) is noninvasive, avoids endotracheal intubation, and potentially avoids the complications associated with intubation. It has been reported in a series of eight preterm infants (mean birth weight 1700 g) with RDS managed with NCPAP. The mean arterial-to-alveolar oxygen tension ratio improved significantly after the treatment, and no complications were reported. Moreover, although the smallest infant in this study was 880 g, the use of the currently available LMA is recommended only for babies above 1500 g. A randomized controlled trial of 26 infants resulted in reduction of FiO 2 in the first 12 hours after surfactant administration, but later no significant difference was found in subsequent need for mechanical ventilation or BPD. However, this study reported several adverse events with the use of LMA. Another randomized trial of 61 patients found that surfactant administration through an LMA reduced the proportion of preterm infants with moderate RDS who required mechanical ventilation compared with standard endotracheal administration following intubation with premedication. The efficacy of surfactant in decreasing RDS severity was similar with both methods. Another randomized trial of 70 infants utilized i-gel for surfactant administration. I-gel is a laryngeal device modeled on the LMA. The study resulted in significantly higher a-A PO 2 after treatment with i-gel compared to INSURE in controls. Thus, although there is accumulating evidence for the administration of surfactant through an LMA or similar device, further research is required to establish the efficacy and risk-versus-benefit ratio of these methods.


Nasopharyngeal Administration of Surfactant


Another noninvasive method of surfactant administration is instillation of surfactant into the nasopharynx during or immediately after delivery and before the first breath. Such instillation is thought to cause the surfactant to be aspirated into the fluid-filled airway as an air–fluid interface is established. A case series of 23 preterm infants of 27 to 30 weeks’ gestation receiving such intrapartum nasopharyngeal instillation of surfactant followed by placement on CPAP immediately after birth (mask CPAP initially followed by NCPAP) demonstrated the feasibility of such administration. However, more evidence is required to prove the efficacy of this approach before it can be used or recommended.


Thin Catheter Endotracheal Administration (Less-Invasive Surfactant Administration)


Instead of an endotracheal tube, this method utilizes a thin catheter that is inserted into the trachea while the patient is spontaneously breathing on a CPAP tube and surfactant is administered through this thin tube, after which the tube is removed. Two systematic reviews summarized the results of individual studies. There was no significant difference regarding mortality or BPD but there was a potential reduction in the need for mechanical ventilation within 72 hours. The Nonintubated Surfactant Application (NINSAPP) multicenter randomized trial found that the intervention did not increase survival without BPD. However, it was associated with increased survival without major complications, specifically a significant reduction of pneumothorax and intraventricular hemorrhage, less need for intubation, and fewer days on mechanical ventilation. Less-invasive surfactant administration is a promising mode of administration of surfactant for the treatment of extremely preterm infants, and the research in this area is active. As of this writing a large randomized multicenter trial (OPTIMIST-A) is being conducted to compare catheter administration of surfactant to sham administration. The trial is expected to conclude in late 2017.


Other Methods


In one randomized clinical trial, the slow infusion of colfosceril using a microinfusion syringe pump over 10 to 20 minutes was compared to manual instillation over 2 minutes. Pump administration resulted in fewer infants with loss of chest wall movement during dosing as well as a smaller increase in peak inspiratory pressure than with hand administration. However, in animals, slow infusion of surfactant into the endotracheal tube results in nonhomogeneous distribution of surfactant in the lung. Therefore, currently, bolus administration of surfactant is preferred. Other methods of administration, such as nebulization or aerosolization and in utero administration to the human fetus, have also been reported. These methods require further clinical testing and may require specialized nebulization equipment. The use of vibrating membrane nebulizers, coupled with appropriate positioning of the interface device, may result in efficient delivery of aerosolized surfactant, but this method also requires further testing and validation.


Chest Position during Administration of Surfactant


In a study in rabbits, pulmonary distribution of intratracheally instilled surfactant was largely determined by gravity, and changing the chest position after instillation did not result in any redistribution of the surfactant. Therefore, for neonates receiving surfactant, keeping the chest in the horizontal position may result in the most even distribution of the surfactant in the two lungs.


Summary of Administration Methods


In summary, based on available evidence, surfactant should be administered in the standard method of aliquots instilled into an endotracheal tube. There is evidence to suggest that the administration of surfactant using a dual-lumen endotracheal tube or through a catheter passed through a suction valve is effective and may cause less dosing-related adverse events than standard methods. The side-port method of administration and the catheter method of administration through the endotracheal tube appear to be equivalent. Less-invasive surfactant administration is a promising method to improve the outcome of extremely preterm infants. More studies are required before firm conclusions can be drawn about the optimal method of administration of surfactant and whether the optimal method is different for different types of surfactant.




Choice of Surfactant Product


Comparison of Animal-Derived Surfactant Extract versus Protein-Free Synthetic Surfactant for the Prevention and Treatment of Respiratory Distress Syndrome


Although both synthetic and animal-derived surfactants are effective, their compositions differ. Animal-derived surfactant extracts contain surfactant-specific proteins that aid in surfactant adsorption and resist surfactant inactivation. Fifteen randomized trials have compared the effects of animal-derived and protein-free synthetic surfactants in the treatment or prevention of RDS. More than 5000 infants were studied in these trials. A systematic review of these trials is available.


Compared to synthetic surfactant without protein, treatment with animal-derived surfactant extracts resulted in a significant reduction in the risk of pneumothorax (typical RR 0.65, 95% CI 0.55-0.77; typical ARD −0.04, 95% CI −0.06 to −0.02) and the risk of mortality (typical RR 0.89, 95% CI 0.79-0.99; typical ARD −0.02, 95% CI −0.04 to 0.00). Animal-derived surfactant extract is associated with an increase in the risk of necrotizing enterocolitis (typical RR 1.38, 95% CI 1.08-1.76; typical ARD 0.02, 95% CI 0.01-0.04) and borderline significant increase in the risk of intraventricular hemorrhage (typical RR 1.07, 95% CI 0.99-1.15; typical ARD 0.02, 95% CI 0.00-0.05), but no increase in grade 3 or 4 intraventricular hemorrhage (typical RR 1.08, 95% CI 0.91-1.27; typical ARD 0.01, 95% CI −0.01 to 0.03). The meta-analysis also supports a marginal decrease in the risk of BPD or mortality associated with the use of animal-derived surfactant preparations (typical RR 0.95, 95% CI 0.91-1.00; typical ARD −0.03, 95% CI −0.06 to 0.00).


In addition to these benefits, animal-derived surfactants have a more rapid onset of action, allowing ventilator settings and inspired oxygen concentrations to be lowered more quickly than with synthetic surfactant. A comparison of physical properties and the results of animal studies also suggest that animal-derived surfactants have advantages over protein-free synthetic surfactants. These properties are attributed to the presence of the surfactant proteins SP-B and SP-C in certain animal-derived surfactants.


The use of animal-derived surfactant preparations should be favored in most clinical situations, because their use results in greater clinical benefits than synthetic surfactants.


Comparison of Protein-Containing Synthetic Surfactant versus Animal-Derived Surfactant Extract for the Prevention and Treatment of Respiratory Distress Syndrome


Clinical trials have compared the effects of synthetic surfactants containing peptides to animal-derived surfactant preparations. These synthetic surfactants do not have the theoretical concerns associated with animal-derived surfactants, namely, transmission of microorganisms, exposure to animal proteins and inflammatory mediators, susceptibility to inactivation, and inconsistent content. Lucinactant, the synthetic surfactant containing an analogue of SP-B, sinapultide, has been compared with beractant in the safety and effectiveness of lucinactant versus Exosurf in a clinical trial of RDS in premature infants (SELECT), a multicenter, masked randomized trial of surfactant prophylaxis in infants of 24 to 32 weeks’ gestation. Lucinactant was also compared with poractant in Surfaxin therapy against RDS, in a multicenter randomized trial (STAR) of surfactant prophylaxis in infants of 24 to 28 weeks’ gestation that was structured as a noninferiority trial. A meta-analysis of these two studies found no significant differences in outcomes between lucinactant and the compared animal-derived surfactant in mortality at 36 weeks’ postmenstrual age (typical RR 0.81, 95% CI 0.64-1.03), chronic lung disease at 36 weeks’ postmenstrual age (typical RR 0.99, 95% CI 0.84-1.18), the composite outcome of mortality or chronic lung disease at 36 weeks’ postmenstrual age (typical RR 0.96, 95% CI 0.82-1.12), or other respiratory outcomes. A decreased risk of necrotizing enterocolitis, a secondary outcome, was noted in infants receiving lucinactant (typical RR 0.60, 95% CI 0.42-0.86; typical RD −0.06, 95% CI −0.10 to −0.01).


However, both trials of lucinactant described above had multiple methodologic problems that undermined their validity, and as of this writing there is no clear evidence of the equivalence or superiority of lucinactant over any animal-derived surfactant product. In March 2012, the Food and Drug Administration approved lucinactant for use in the United States. Further research is required to elucidate the role of newer surfactants in the prevention or treatment of RDS.


Comparison of Protein-Containing Synthetic Surfactant versus Protein-Free Synthetic Surfactant for the Prevention and Treatment of Respiratory Distress Syndrome


In the SELECT trial, the randomized trial of lucinactant, in which lucinactant was compared with beractant, lucinactant was also compared to colfosceril. Infants who received protein-containing synthetic surfactant compared to protein-free synthetic surfactant did not demonstrate significantly different risks of mortality at 36 weeks’ postmenstrual age (PMA) (RR 0.89, 95% CI 0.71-1.11), chronic lung disease at 36 weeks’ PMA (RR 0.89, 95% CI 0.78-1.03), or the combined outcome of mortality or chronic lung disease at 36 weeks’ PMA (RR 0.88, 95% CI 0.77-1.01). Regarding the secondary outcome of RDS at 24 hours of age, a decrease in the incidence was demonstrated in the group that received lucinactant (RR 0.83, 95% CI 0.72-0.95).


Comparison of Different Types of Bovine Surfactants


Two prevention studies and seven treatment studies compared bovine lung lavage surfactant extract to modified bovine minced lung surfactant extract. The meta-analysis of the prevention trials, representing high-quality evidence, found no significant difference in death or chronic lung disease (typical RR 1.02, 95% CI 0.89-1.17; typical RD 0.01, 95% CI −0.05 to 0.06). Analysis of the treatment trials also found no significant differences between these two types of bovine surfactants in death or chronic lung disease (typical RR 0.95, 95% CI 0.86-1.06; typical RD −0.02, 95% CI −0.06 to 0.02, high-quality evidence).


Comparison of Porcine and Bovine Surfactants


Nine treatment studies compared modified bovine minced lung surfactant extract with porcine minced lung surfactant extract. A meta-analysis of these studies found a significant increase in mortality prior to hospital discharge (typical RR 1.44, 95% CI 1.04-2.00; typical RD 0.05, 95% CI 0.01-0.10) in patients treated with modified bovine surfactant extract compared with porcine minced lung surfactant extract. Other outcome parameters like death or oxygen requirement at 36 weeks’ PMA (typical RR 1.30, 95% CI 1.04-1.64; typical RD 0.11, 95% CI 0.02-0.20), receiving more than one dose of surfactant (typical RR 1.57, 95% CI 1.29-1.92; typical RD 0.14, 95% CI 0.08-0.20), and patent ductus arteriosus requiring treatment (typical RR 1.86, 95% CI 1.28-2.70; typical RD 0.28, 95% CI 0.13-0.43) also favored treatment with porcine minced lung surfactant. The dose of beractant was uniformly 100 mg/kg across all five studies. When only studies that used a 100 mg/kg dose of poractant were considered, the reduction in mortality prior to discharge and risk of death or oxygen requirement at 36 weeks’ PMA were not statistically significant. It is uncertain that the statistical difference between the two types of surfactants was related to the source of extraction (porcine vs bovine) or to the higher initial dose of porcine surfactant.

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Jan 30, 2019 | Posted by in PEDIATRICS | Comments Off on Pharmacologic Therapies I: Surfactant Therapy
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