A Multicenter, Randomized, Controlled Trial Comparing Surfaxin (Lucinactant) Lavage With Standard Care for Treatment of Meconium Aspiration Syndrome
Objective. Infants with meconium aspiration syndrome (MAS) have marked surfactant dysfunction. Airways and alveoli of affected neonates contain meconium, inflammatory cells, inflammatory mediators, edema fluid, protein, and other debris. The objective of this study was to compare treatment with bronchoalveolar lavage using dilute Surfaxin with standard therapy in a population of newborn infants with MAS.
Methods. Inclusion criteria were 1) gestational age ≥35 weeks, 2) enrollment within 72 hours of birth, 3) diagnosis of MAS, 4) need for mechanical ventilation, and 5) an oxygenation index ≥8 and ≤25. Subjects were randomized to either lavage with Surfaxin or standard care (2:1 proportion). In lavaged infants, a volume of 8 mL/kg dilute Surfaxin (2.5 mg/mL) was instilled into each lung over approximately 20 seconds followed by suctioning after 5 ventilator breaths. The procedure was repeated twice. The third and final lavage was with a more concentrated solution (10 mg/mL) of Surfaxin.
Results. Twenty-two infants were enrolled (15 Surfaxin and 7 control). Demographic characteristics were similar. There were trends (not significant) for Surfaxin-lavaged infants to be weaned from mechanical ventilation earlier (mean of 6.3 vs 9.9 days, respectively), as well as to have a more rapid decline in their oxygenation indexes compared with control infants, the latter difference persisting for the 96-hour-long study period. The therapy was safe and generally well tolerated by the infants.
Conclusions. Dilute Surfaxin lavage seems to be a safe and potentially effective therapy in the treatment of MAS. Data from this investigation support future prospective, controlled clinical trials of bronchoalveolar lavage with Surfaxin in neonates with MAS.
Meconium aspiration syndrome (MAS) is a severe respiratory disorder in neonates for which there is no specific therapy.1,2 Each year, approximately 25 000 newborn infants in the United States develop MAS involving progressive respiratory distress, hypoxia, hypercapnia, and acidosis and need intensive respiratory therapy. Extracorporeal membrane oxygenation (ECMO) is a costly and invasive procedure associated with a high degree of morbidity. Since the mid-1980s, MAS has been the most common disorder among infants who require ECMO for survival (approximately 35% of cases), although the number has been decreasing in recent years.3 Mortality rates for MAS generally range from 3% to 12%.1,2 Therefore, it would be of benefit to mitigate the course of this disorder.
The pathophysiologic mechanisms involved in the development of MAS include mechanical obstruction of airways, inflammatory cell infiltration, release of vasoconstrictive substances and inflammatory mediators, protein leakage into airways, and inactivation of surfactant.2,4–6 Constituents of meconium that may contribute to the alteration of the physical properties of surfactant include fatty acids, cholesterol, bile salts, bilirubin, blood, and proteolytic enzymes. There are likely multiple mechanisms by which meconium adversely affects endogenous surfactant.2 Logically, therapy with bolus doses of exogenous surfactant has been tried in an attempt to ameliorate the course of MAS. Anecdotal reports have been encouraging,7,8 and a small, randomized, controlled trial demonstrated significant improvement with such therapy.9
A novel treatment approach for MAS is that of lung lavage using dilute surfactant. Theoretically, airway lavage could remove noxious material from the lungs (meconium, neutrophils, proteinaceous debris, etc), while leaving behind a therapeutic amount of functional surfactant. Ogawa et al10 as well as Lam and Yeung11 reported uncontrolled, anecdotal experience using small volumes of dilute bovine surfactant to lavage 4 and 6 neonates with MAS, respectively. Both groups noted clinical improvement in these infants. In 2 animal models of MAS, Cochrane et al12 used a more vigorous lavage approach and substantially improved pulmonary function. The latter group performed their lavages with dilute Surfaxin (Discovery Laboratories, Inc, Doylestown, PA), a surfactant that contains a peptide mimic of human surfactant protein B.
The objective of this investigation was to assess the safety and potential efficacy of an approach similar to that of Cochrane et al in newborn infants with MAS. This report reflects the first randomized, controlled trial of bronchoalveolar lavage (BAL) using dilute surfactant for the treatment of neonates with MAS.
This was an open-label, controlled phase I/II trial in which 22 infants with MAS were randomized in a 1:2 ratio to either standard care (SC) or bronchoalveolar lavage with Surfaxin (1 SC:2 BAL). A phase I trial assesses safety of the drug and the procedure, whereas a phase II trial evaluates for elements of efficacy. The protocol was approved by the institutional review boards of the 15 participating centers. The study was performed under the United States Food and Drug Administration (FDA) Investigational New Drug number 40287. Parents of affected infants received counseling and had to provide written informed consent for their child to be enrolled in the trial. Inclusion criteria were 1) diagnosis of MAS; 2) treatment with conventional positive pressure ventilation; 3) postnatal age ≤72 hours; 4) gestational age ≥35 weeks; 5) an oxygenation index (OI) ≥8 and ≤25 on at least 2 of 3 consecutive arterial blood gas readings within a 3-hour period, with the last reading no more than 60 minutes before randomization (oxygenation index was defined as the product of the fraction of inspired oxygen (Fio2) and the mean airway pressure multiplied by 100 and divided by the Pao2); and 6) written informed consent from the parent(s). Exclusion criteria were 1) congenital anomalies likely to affect the primary or any secondary endpoints, 2) uncontrollable air leaks (eg, Pneumothorax unresponsive to thoracostomy drainage), 3) pulmonary hemorrhage, 4) hydrops fetalis (immune or nonimmune), 5) prolonged rupture of the fetal membranes (≥3 weeks), or 6) known severe intracranial hemorrhage (grade 3 or 4). MAS was defined as respiratory distress in an infant born through meconium-stained amniotic fluid with roentgenographic findings consistent with MAS and whose symptoms could not be otherwise explained.1,2
In surfactant-treated infants, an inline tracheal suction device (Trach Care Neonatal Y; Ballard Medical Products, Draper, UT) with a side arm for the administration of Surfaxin was positioned between the endotracheal tube and the ventilator tubing connector. The suction tubing was connected to a calibrated trap so that the volume of retrieved fluid after suctioning could be measured. Surfactant-treated infants were sedated before dosing to allow for proper ventilation; paralysis-inducing medications were used at the discretion of the site investigator. Ten minutes before the administration of the Surfaxin, ventilator parameters were adjusted to the following settings: Fio2 = 1.0; positive end expiratory pressure (PEEP) = 6 to 8 cm H2O; and sufficient positive inspiratory pressure for lung inflation (the ventilator rate was held constant). Surfaxin was administered within 30 minutes of randomization. Each of the infant’s lungs was lavaged 3 separate times, as per Table 1 (lavages 1A and 1B through lavages 3A and 3B).
The initial 2 series of lavages (lavages 1A and 1B, lavages 2A and 2B) were with 8 mL/kg of a 2.5 mg/mL concentration of Surfaxin, whereas the third series (lavages 3A and 3B) was with 8 mL/kg of a 10 mg/mL concentration of Surfaxin. For the lavage instillation, the patient’s bed was adjusted from horizontal to an angle of approximately 30 degrees, head up. Infants were then positioned in the right lateral decubitus position (right side down). This positioning was to ensure that the majority of the instilled Surfaxin would be administered into the dependent lung. The ventilator was transiently adjusted to “PEEP only” (at 6–8 cm H2O), while the Surfaxin was instilled via the lavage port into the endotracheal tube over a period of 15 to 25 seconds. Once instillation was completed, positive pressure ventilation was restarted and the infant’s bed was repositioned to an angle of approximately 30 degrees, head down. After 5 ventilator breaths, the inline catheter was rapidly advanced to a position approximately 5 mm past the end of the endotracheal tube. Suction was activated (at −80 to −120 mmHg negative pressure) for no more than 10 seconds. The inline catheter was withdrawn, and the infant was moved back to the horizontal position. Positive pressure ventilation was continued throughout the suctioning procedure. Once the child was stable (peripheral arterial oxygen saturation [Spo2] no more than 5% less than the prelavage 1A baseline value), the suctioning procedure was repeated. After stabilization, a third suctioning was performed if the site investigator believed that it was clinically appropriate (indications for suctioning were retrieval of < 50% of instilled volume withdrawn or fluid still being retrieved at the end of the 10-second suction period). The total retrieved fluid volume was measured and recorded. Once patients recovered to “stability” (stability was defined as heart rate and blood pressure within 20% of prelavage 1A baseline and Spo2 no more than 5% less than prelavage 1A baseline), they were positioned in the left lateral decubitus position and the lavage procedure as previously described was repeated (lavage 1B). The infant was allowed to stabilize after each lavage. Stability had to be achieved as previously defined before a subsequent lavage could be performed. The subsequent lavages (2A, 2B, 3A, and 3B) were performed identical to lavages 1A and 1B except for the higher surfactant concentration (10 mg/mL) used during lavages 3A and 3B. After completion of the BAL procedure, ventilator PEEP was maintained at a minimum of 6 to 8 cm H2O for at least 120 minutes or longer if desired by the site investigator. No additional postlavage suctioning was mandated. Postlavage suctioning was performed only for clinical reasons as routinely performed in the various participating neonatal intensive care units.
The SC patients received therapies including oxygen and conventional positive pressure ventilation, as well as the use of alkalosis, paralysis, vasopressors, or sedation at the discretion of the study site investigator. Rescue therapies, such as high-frequency ventilation, bolus surfactant, inhaled nitric oxide, or ECMO, were not allowed in either group unless patients met treatment failure criteria. Treatment failure for both the Surfaxin and the SC groups occurred when the infant achieved either an OI >25 or an OI that was increased > 50% above baseline as ascertained on 2 of 3 blood gas readings within a 3-hour period. Rescue therapy (as defined previously) could be initiated at the discretion of the site investigator only after the patient met treatment failure criteria.
The primary efficacy endpoint was the incidence of treatment failure, which was defined as either an OI >25 or an increase in OI to >50% above baseline (whichever came first), as ascertained on at least 2 arterial blood gas readings within a 3-hour period. Secondary endpoints included the incidence of MAS-related death in the first 28 days of life, sustained improvement in oxygenation (decrease in OI over time), need for rescue therapies, and the number of days to extubation.
In addition, follow-up was conducted to provide morbidity, neurodevelopmental outcome, and safety data through 1 year of age for full-term infants who participated in this study. This follow-up study examined the neurodevelopment, growth, and overall health of participating infants. At 3 and 6 months of age, each infant’s parents or guardians were interviewed by telephone to obtain information concerning the interinterval history. Interinterval history reflected the health status of the child from the last time he or she was assessed until the time of the interview. It included the medical and pulmonary history of the child, as well as use of any medications. At 1 year of age, infants returned to the participating center for an interinterval medical history (concerning respiratory or other illnesses and hospitalizations), evaluation of current respiratory status and physical examination (including growth parameters), complete neurologic examination, assessment of neurodevelopmental status (using the Bayley Scales of Infant Development II13), and recording of adverse events and concomitant medications/therapies.
There was no formal sample size calculation for this pilot study, which assessed safety and potential of efficacy. Members of the Scientific Advisory Board (T.E.W., N.N.F., T.A.M., F.L.M., and C.G.C.) and a biostatistician (H.T.) met 6 months before the initiation of the investigation. The group consensus was that a pilot trial of 20 to 30 total patients (2 of 3 of whom were lavaged) would be sufficient for a pilot project to assess safety of the procedure and elements of efficacy. Data analyses included all randomized patients on an intent-to-treat basis and used 2-sided tests. Treatment groups were compared with respect to the categorical primary efficacy variable, treatment failure, using the Cochran-Mantel-Haenszel test for general association. Continuous variables were compared using analysis of variance models. Nonparametric tests were used when appropriate.
A total of 22 patients were enrolled in the trial from 9 of the participating 15 sites. Fifteen infants were randomized to Surfaxin lavage, and 7 were randomized to SC. We describe baseline characteristics of the study population in Table 2. The groups were similar for most demographic characteristics. However, all of the infants in the SC group were outborn, compared with 8 of 15 Surfaxin infants. Nevertheless, there were no differences in the severity of illness between the outborn and inborn infants (neither ventilator settings nor OIs were higher, whereas Apgar scores were similar). In addition, there were no differences between groups in the use of standard therapies (alkalosis, sedation, etc). Before randomization, the groups were similar in the number treated with paralysis (8 of 15 Surfaxin vs 3 of 7 SC), those experiencing pneumothoraxes (3 of 15 Surfaxin vs 0 of 7 SC), previous treatment with high-frequency ventilation (1 of 15 Surfaxin vs 1 of 7 SC), and those treated with bolus surfactant (1 of 15 Surfaxin vs 2 of 7 SC). The lavage procedures were generally accomplished within 50 to 60 minutes. Heart rate and blood pressure were stable during BAL. After Surfaxin instillation, during the suctioning procedure Spo2 levels transiently dropped to the range of 73% to 89%, occasionally as low as 58%. Decreased oxygen saturation levels generally lasted for <1 minute and were most often lowest during the third set of lavages.
Three patients failed to complete Surfaxin lavage therapy. The procedure was stopped after the second series of lavages in 1 infant because of transient hypoxemia. This infant had concomitant congenital herpes simplex virus type 1 infection that rendered her unstable. The infection was not known at the time of enrollment (culture results were available 2 days after the procedure). The site investigator considered this infection to be the major contributor to the child’s hypoxemia. In a second Surfaxin-treated infant, the procedure was halted because of hypotension after the second series of lavages. This infant had concurrent disseminated Gram-negative bacterial infection (Escherichia coli). The blood culture results were available only approximately 18 hours after the procedure. The latter type of severe infection frequently lowers neonates’ blood pressure and was believed by the site investigator to be the major contributor to the infant’s hypotension. There were no systemic infections in the remaining 13 lavaged patients or 7 SC infants. A third patient completed only the first series of lavages. In this case, unscheduled arterial blood gases obtained between lavages 1B and 2A revealed OI values >50% above baseline (ie, treatment failure criteria). The treating investigator responded by halting the procedure.
In Table 3, we describe the mean amount of Surfaxin that was retrieved with suctioning after each lavage and the percentage of fluid removed compared with what was instilled. Overall, approximately 50% of instilled dilute Surfaxin was retrieved. The least amount of fluid was obtained after the first series of Surfaxin instillation (lavages 1A and 1B). The amount retrieved was substantially greater among infants who were both sedated and paralyzed compared with those who were only sedated. In one third of the lavaged infants, the retrieved fluid was pink in color rather than brown. Site analysis revealed that the fluid contained blood. The latter infants tended to be older at the time of enrollment. In no case was there active, ongoing pulmonary hemorrhage with bright red blood. From the mean amounts of fluid retrieved after each lavage, we estimate that 110 mg of surfactant phospholipid per kilogram of birth weight on average was left inside each lavaged infant’s lungs after the procedure.
Figure 1 graphically depicts the course of the oxygenation index during the initial 96 hours after randomization. Baseline values were obtained before randomization. Surfaxin-lavaged neonates had trends toward more rapid and more sustained improvements in oxygenation compared with the SC infants. These differences did not reach statistical significance.
Table 4 presents the outcome characteristics of the enrolled subjects through the 28-day study period. There were no deaths in either group, whereas a single infant in each group required ECMO. Treatment failure by OI criteria occurred in 5 (33%) of the lavaged infants compared with 2 (29%) of the control subjects. In addition, some form of rescue therapy was used in 7 (47%) of the lavaged infants compared with 4 (57%) of the control patients. Two of the 5 Surfaxin treatment failure infants had the aforementioned infections, and a third met failure criteria when she went into congestive heart failure as a result of a congenital heart anomaly that was not diagnosed before enrollment. Nevertheless, the latter patient’s MAS initially improved radiographically and clinically (markedly lower OIs) in the initial 12 to 18 hours after lavage. However, the therapy may have hastened the infant’s subsequent congestive heart failure, as the “improved” lungs likely had lower pulmonary pressures, which allowed the left-to-right shunting that was a consequence of the anomaly. Infants in the Surfaxin-treated group were weaned off mechanical ventilation approximately 3 days earlier than the SC subjects (median 4.6 vs 7.6 days), a trend that was not statistically significant.
We assessed various aspects concerning safety of the lavage procedure. Five (33%) of 15 infants were hand-ventilated during the procedure to enhance recovery from transient oxygen desaturation. Three neonates (20%) gagged at least once, and 4 (27%) coughed during the procedure. All of the latter infants were only sedated and not paralyzed during lavage. One Surfaxin subject developed a pneumothorax 4 days after the procedure. The site investigator did not consider this to be related to the lavage. There were no differences between groups in the proportion of infants with reported adverse experiences. A single serious adverse experience of oxygen desaturation in the infant with herpes simplex virus infection was reported as being “probably related” to the lavage therapy.
Follow-up through 1 year of age revealed no significant differences between groups in the number of hospitalizations or in the number or type of intercurrent illnesses (including respiratory illnesses). No infants died. In addition, in all children, growth was similar for the 3 measured parameters of weight, length, and head circumference. There were no differences between groups in the MDI and PDI scores assessed with the Bayley Scales of Infant Development II.13
MAS is a disorder of term-gestation infants that is seen relatively frequently. The FDA has not approved any specific therapies for MAS. In this trial, Surfaxin-lavaged infants tolerated the BAL procedure. Each of the 9 investigators who enrolled patients believed that both the drug and the procedure seemed to be safe and tolerated. Compared with SC infants, those who were lavaged had trends for more rapid and sustained improvement in oxygenation, as well as fewer days on mechanical ventilation. In addition, no serious adverse experiences were believed to be “highly probably related” (FDA terminology) to either the drug or the procedure. The sole “ probably-related” serious adverse experience (hypoxemia) occurred in a patient with a severe congenital infection that may have caused hypoxemia on its own accord. The infants enrolled in this trial were moderately sick with MAS (OI values ≤25). Infants with more severe disease were not included in this pilot trial. Infants with severe MAS often have concomitant persistent pulmonary hypertension that may be exacerbated by hypoxemia. Therefore, infants with more severe MAS (eg, OI levels >25) may tolerate this procedure less well than did the subjects in this study.
Surfaxin (lucinactant) is a surfactant that contains sinapultide, the KL4 peptide that is a mimic of human surfactant protein B. In an aqueous dispersion, the chemically synthesized KL4 peptide is combined with the phospholipids dipalmitoylphosphatidylcholine and palmitoyl-oleoyl phosphatidylglycerol, as well as palmitic acid, to form Surfaxin.14–16 Surfaxin (developmental name: KL4-surfactant) for this trial was provided by Discovery Laboratories, Inc. Herting et al17 found KL4-surfactant to be better able both to resist inactivation by meconium and to lower surface tension compared with the bovine surfactants Survanta (Ross Laboratories, Columbus, OH) and Alveofact (Boehringer Ingelheim, Ingelheim, Germany) as well as the porcine surfactant Curosurf (Chiesi Pharmaceuticals, Parma, Italy). Others have found Surfaxin to be more resistant to both oxidative18 and protein19 inactivation compared with Survanta. Surfaxin has previously been shown to be safe and efficacious in premature human infants with respiratory distress syndrome.20 The safety and efficacy profiles of the drug in the latter trial were similar to those of commercially available bovine surfactants.21 In addition, a recent report described adults who had acute respiratory distress syndrome and were treated with dilute Surfaxin lavage via bronchoscopy.22 This similar concept of lung cleansing and surfactant restoration in adults was found to be safe and well tolerated, as well as to result in improved oxygenation and lower ventilator settings. In the current trial, the average amount of phospholipid left in each lavaged child’s lungs (110 mg/kg) was similar to that of a standard dose of Survanta (100 mg/kg) given to premature infants with respiratory distress syndrome.
Meconium inactivates surfactant4–6 and decreases production of surfactant proteins A and B.23 Clinicians have tried to overcome these effects by instilling exogenous surfactant.7–9 Most reports describing such therapy are anecdotal in nature. In many of these reports, no significant improvements have been noted until a second or third dose of surfactant was administered to the infant with MAS. Findlay et al9 performed a small, randomized, controlled trial to assess exogenous surfactant administration in neonates with MAS, using bovine surfactant at a higher-than-standard dose. In that trial, the surfactant was not given as a bolus; rather, it was continuously infused over a period of approximately 20 minutes. Surfactant-treated infants were significantly less likely to have air leaks or require ECMO, as well as to have fewer days of mechanical ventilation, oxygen therapy, and hospitalization. Lotze et al24 performed a larger trial using surfactant therapy in term-gestation infants with severe respiratory failure (approximately half of the 328 enrolled infants had MAS as the cause of their respiratory failure). The treated infants received 4 standard bolus doses of bovine surfactant (100 mg/kg). Although surfactant-treated infants were significantly less likely to require ECMO, Lotze et al were unable to demonstrate differences in air leaks or in the duration of mechanical ventilation, oxygenation, or hospitalization.
Paranka et al25 first described surfactant lavage in a piglet model of MAS. Ohama et al26 performed similar therapy in an adult rabbit model of the disorder. Both studies suggested that dilute surfactant was an effective agent in removing meconium and other debris, as well as an effective surface tension–lowering compound. Meister et al27 performed dilute surfactant lavages in a piglet model of acute lung injury. These authors instilled large volumes of dilute surfactant (35 mL/kg) and found substantial improvements in oxygenation. In an uncontrolled study, Ogawa et al10 reported experience in lavaging 4 neonates with MAS. They used a dilute suspension of bovine surfactant (6 mg/mL) administered 5 times in small volumes (1 mL/kg). All infants improved after this therapy. Lam and Yeung11 subsequently reported their anecdotal experience in lavaging 6 infants with MAS. They administered an average of 26 doses (2 mL at a time) of a 5 mg/mL suspension of bovine surfactant. Compared with historic controls, Lam and Yeung found the lavaged infants to have a more rapid improvement in oxygenation and to be weaned off mechanical ventilation 3 days sooner. In addition, these authors reported that blood-tinged fluid was suctioned from 2 of the 6 infants, similar to what we describe. We and others have previously reported localized pulmonary hemorrhage after meconium aspiration in both fetal28 and postnatal12,29 animal models of MAS. Moreover, Berger et al30 found that MAS is the leading cause of pulmonary hemorrhage in term-gestation infants. We suspect that the longer the meconium is present in the lungs, the greater the likelihood it may cause some localized bleeding.
Cochrane et al12 devised a more vigorous approach to lavage therapy in animal models of MAS. These investigators performed a series of 3 BALs in each lung using dilute Surfaxin. Compared with control animals, lavaged subjects had a more rapid, sustained improvement in oxygenation, as well as rapid clearing of their chest roentgenograms. In addition, Cochrane’s group compared histologic findings with 3 control groups: 1) MAS without lavage, 2) MAS treated with saline lavage, and 3) MAS treated with bolus surfactant. The lungs of the Surfaxin-lavaged animals were better expanded and contained substantially less debris (meconium, leukocytes, protein, red blood cells) than the other groups. We adopted this group’s approach for this initial prospective, randomized, controlled trial of surfactant lavage in infants with MAS. We acknowledge that the SC group did not undergo the increased ventilator settings that the lavage group underwent at the time of the procedure. We do not believe that this factor affected outcomes. Indeed, an advantage of using OI as a comparator is that it encompasses parameters that reflect ventilator settings (Fio2 and mean airway pressure).
This unique approach to the treatment of the MAS seems to be safe and generally well tolerated. In a dilute form, Surfaxin is easily administered and suctioned in volumes sufficient to remove injurious debris, as well as to provide good, functional surfactant while the lung heals. We believe that the data from this trial support additional clinical investigation of BAL with Surfaxin in neonates with MAS. The FDA has approved a large phase III trial to assess further the safety and efficacy of this approach to the disorder.
This study was supported by Discovery Laboratories, Inc, Doylestown, PA. In addition, this trial was supported, in part, by a grant from the Office of Orphan Products Development of the FDA, FD-R-001424-01.
The following sites and investigators participated in this trial but did not enroll any patients: Pennsylvania Hospital (Soraya Abbasi), Philadelphia, Philadelphia; University of Texas Health Science Center at San Antonio (Robert Castro), San Antonio, Texas; Schneider Children’s Hospital (Dennis Davidson), New Hyde Park, New York; Loma Linda University Medical Center (Andrew Hopper), Loma Linda, California; and the University of Texas at Houston Medical School (Fernando Moya), Houston, Texas.
We acknowledge the help of the following individuals: Raymond Malloy, RRT; Diane Suevo, RN, CRNP; Christopher Henderson, RRT; Maynard Rasmussen, MD; Randy Buckley, RRT; Rosemary Higgins, MD; Pamela Angelus, RN; and Michael McCoy, ARNP.
- Received December 22, 2000.
- Accepted January 17, 2002.
- Reprint requests to (T.E.W.) SUNY Stony Brook, Pediatrics, HSC-11-060, Stony Brook, NY 11794-8111. E-mail:
During the period in which the trial took place, Dr Wiswell was an employee of Discovery Laboratories, Inc. Dr Mastrioianni, Dr Marcy, and Dr Tsai are employees of Discovery Laboratories, Inc. Dr Wiswell, Ms Revak, and Dr Cochrane own stock in Discovery Laboratories, Inc, but do not have >1% of the shares outstanding in the company’s stock.
- ↵ECMO Registry of the Extracorporeal Life Support Organization (ELSO). Ann Arbor, MI: ELSO; July 2001
- ↵Sun B, Curstedt T, Robertson B. Surfactant inhibition in experimental meconium aspiration syndrome. Acta Paediatr Scand.1993;82 :182– 189
- ↵Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment in full-term newborns with respiratory failure. Pediatrics.1991;87 :101– 107
- ↵Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics.1996;97 :48– 52
- ↵Ogawa Y, Ohama Y, Itakura Y, et al. Bronchial lavage with surfactant solution for the treatment of meconium aspiration syndrome. J Jpn Med S C Biol Interface P N.1996;26 :179– 184
- ↵Lam BCC, Yeung CY. Surfactant lavage for meconium aspiration syndrome: a pilot study. Pediatrics.1999;103 :1014– 1018
- ↵Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio, TX: The Psychological Corporation; 1993
- ↵Cochrane CG, Revak SD. Pulmonary surfactant protein B (SP-B): structure-function relationships. Science.1991;254 :566– 568
- ↵Andersson S, Kheiter A, Merritt TA. Oxidative inactivation of surfactants. Lung.1999;177 :179– 189
- ↵Bloom BT, Kattwinkel J, Hall RT, 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
- ↵Cleary GM, Antunes MJ, Ciesielka DA, et al. Exudative lung injury is associated with decreased levels of surfactant proteins in a rat model of meconium aspiration. Pediatrics.1997;100 :998– 1003
- ↵Wiswell TE, Popek E, Barfield WD, Peabody S. The effect of intra-amniotic meconium on histologic findings over time in a fetal rabbit model [abstract 1550]. Pediatr Res.1994;35 :261A
- Copyright © 2002 by the American Academy of Pediatrics