Vitamin A Supplementation by Endotracheal Application of a Nano-encapsulated Preparation Is Feasible in Ventilated Preterm Lambs.

BACKGROUND: Vitamin A (VA) is crucial for lung growth and development. In premature infants, inadequate VA levels are associated with an increased risk of bronchopulmonary dysplasia (BPD). Intramuscular VA supplementation has been shown to decrease the incidence of BPD, but is not widely used in the clinical setting due to concerns about feasibility and pain. We studied VA kinetics, distribution, and the induction of early genetic expression of retinoid homeostatic genes in the lung after endotracheal and intravenous application in a preterm lamb model. METHODS: Lambs were delivered prematurely after 85% of gestation, intubated, and ventilated for 3 hours. The animals were randomized to receive no VA ("control"), a bolus of VA intravenously ("i.v."), or VA endotracheally directly after administration of surfactant ("e.t."). RESULTS: Animals treated with VA endotracheally directly after administration of surfactant showed significant increases of VA in serum and lung compared to controls. Animals treated with a bolus of VA intravenously showed significant increases of VA in serum, lung, and liver; however, peak serum concentrations and mRNA levels of homeostatic genes raised concerns about toxicity in this group. CONCLUSIONS: Endotracheal VA supplementation in preterm lambs is feasible and might offer advantages in comparison to i.v. Further studies are warranted to explore biological effects in the context of BPD.

Effects of Natural versus Synthetic Surfactant with SP-B and SP-C Analogs in a Porcine Model of Meconium Aspiration Syndrome.

BACKGROUND: Meconium displaces surfactant from the alveolar surface and inhibits its function. The development of active synthetic surfactants is complicated, especially to synthesize the hydrophobic surfactant proteins SP-B and SP-C. A synthetic surfactant, CHF5633 containing SP-B and SP-C analogs, has been designed to act similarly to the natural surfactant poractant alfa. OBJECTIVE: To test the resistance to meconium inactivation of CHF5633 compared to poractant alfa. Secondary outcome measurements were respiratory and inflammatory parameters. METHODS: Twenty-six newborn pigs, bodyweight 1.4-2.0 kg were randomized to receive either poractant alfa or CHF5633. After anesthesia, surgery and final stabilization, meconium was instilled endotracheally followed by surfactant. Bronchial lavage fluid was obtained before intervention and every second hour. Respiratory parameters were registered and blood samples drawn before intervention and every hour. RESULTS: Surfactant was inactivated in both groups 6 h after meconium instillation, but CHF5633 was more resistant than poractant alfa in terms of lipid peroxidation. Respiratory parameters were similar in both groups. Inflammatory and hemostatic parameters differed between groups, suggesting that the surfactants may play different roles in the meconium-induced inflammatory process. Due to the differential effects and complex pattern observed, the data do not indicate that one of the surfactants was superior with respect to inflammatory and hemostatic responses. CONCLUSION: This study indicates that CHF5633 is as efficient as poractant alfa in experimental meconium aspiration syndrome.

Effects of different pulmonary surfactants in the prevention of postoperative intraabdominal adhesion formation.

BACKGROUND: After abdominal surgery, the formation of postoperative adhesion is a serious problem. The aim of the study is to evaluate the efficacy of 2 different pulmonary surfactants, poractant and beractant, on adhesion prevention in an experimental model. MATERIALS AND METHODS: An experimental intraabdominal adhesion model was created in 18 adult female rats by cecal abrasion. The rats were randomly assigned to 3 groups. Group I received no further treatment, whereas groups II and III received intraperitoneal poractant and beractant, respectively, before closing the incision. On the 15th postoperative day, all rats underwent relaparotomy, intraabdominal adhesions were scored macroscopically according to Canbaz scoring system, and the cecum in each animal was evaluated microscopically. RESULTS: The median adhesion scores of group II and III rats were significantly lower when compared with group I (P = .02). Group III had a lower median adhesion score than did group II, but this did not reach significance (P > .05). CONCLUSION: These observations suggest that intraperitoneal instillation of both pulmonary surfactants is associated with lower adhesion scores, higher adhesion-free cases, and improved histologic findings.

Impact of providing vitamin A to the routine pulmonary care of extremely low birth weight infants.

OBJECTIVE: The objective of this study was to determine if the continued use of vitamin A in a nursery utilizing early surfactant and nasal continuous positive airway pressure (CPAP) was warranted. STUDY DESIGN: A retrospective, cohort study of appropriately sized, preterm neonates weighing ≤1000 g at birth was conducted. Two time periods were compared: Pre-Vitamin A was composed of extremely low birth weight who were routinely cared for with early nasal CPAP (n = 76); and Post-Vitamin A (n = 102) consisted of ELBWs who were cared for similar to Pre-Vitamin A, but with the addition of vitamin A. Outcome variables included the incidence of BPD and other pulmonary and major neonatal morbidities. RESULTS: Between Pre-Vitamin A and Post-Vitamin A the incidence of moderate to severe BPD decreased by 11%, from 33% to 22% (p = 0.2). No difference was found in the number of ventilator days or in the incidence of any other neonatal morbidity or mortality, including intraventricular hemorrhage, necrotizing enterocolitis, or patent ductus arteriosus requiring surgical ligation. CONCLUSION: In a neonatal unit utilizing early surfactant followed by nasal CPAP at delivery, supplementing extremely premature neonates with vitamin A demonstrated a trend towards a decrease in the incidence of moderate to severe BPD; however, this change requires a larger sample to verify in the future.

Estrategias de prevención y tratamiento en displasia broncopulmonar / Strategies for prevention and treatment of broncopulmonary dysplasia

Bronchopulmonary Dysplasia (BPD) continues to be a highly frequent sequela of low birth weight infants. This, despite the many recent advances in perinatal medicine that include antenatal steroids, exogenous surfactant, new strategies for mechanical respiratory support, parenteral nutrition improvements and a more judicious use of supplemental oxygen. The purpose of this review is to analyze and describe the recent advances in the prevention and management of BPD. New preventive therapies have been developed, and vitamin A and caffeine administration have been shown to diminish the incidence of this disorder. Postnatal corticosteroids can also be useful, but due to their negative long-term neurological effects, these medications are not currently recommended. Corticosteroid administration in established BPD can decrease the need for mechanical ventilation and improve lung function. Other preventive interventions such as antioxidant administration and nitric oxide inhalation are currently being investigated. The persistence of the ductus arteriosus is associated with increased risk of BPD, therefore early pharmacologic closure can play a role in preventing this disorder. New modalities of mechanical ventilation, such as synchronized and high frequency ventilation, have not been shown to decrease the incidence of this disease. While a discussion regarding the best type of ventilation to be used still remains, the consensus is that that the lowest inspiratory pressure and lowest oxygen concentration necessary should be utilized to maintain adequate gas exchange. Optimal level of arterial oxygen saturation in premature infants is still controversial, but the current recommended range is between 88 percent and 95 percent. Summary: Vitamin A and caffeine are both effective drugs in the prevention of BPD. The role of early closure of the ductus arteriosus and the use of postnatal administration of corticosteroids in the prevention of BPD are...

La Displasia Broncopulmonar (DBP) es una de las secuelas más frecuentes que afecta al recién nacido de muy bajo peso. Esto es, a pesar de los avances de la medicina perinatal de los últimos años, como la administración de corticoides antenatales, surfactante exógeno, nuevos modos y estrategias de ventilación mecánica, mejoría de la nutrición parenteral y el uso más cuidadoso del oxígeno. El objetivo de la presente revisión es analizar y describir los recientes avances en la prevención y tratamiento de la DBP. Nuevas terapias preventivas han emergido, habiéndose demostrado que la administración de vitamina A y cafeína disminuyen la incidencia de esta afección. Los corticoides postnatales también disminuyen la incidencia de esta enfermedad, pero por sus efectos neurológicos a largo plazo, no se recomiendan actualmente. La administración de corticoides en la DBP establecida reduce el uso de ventilación mecánica y mejora la función pulmonar del recién nacido. Otras intervenciones preventivas como la administración de antioxidantes y óxido nítrico inhalado están siendo estudiadas. La persistencia del ductus arterioso se ha asociado a displasia, por lo cual, el cierre farmacológico precoz podría tener relevancia en la prevención de esta. Los nuevos modos de ventilación mecánica, como la ventilación sincronizada y la ventilación de alta frecuencia, no han disminuido la incidencia de esta enfermedad. Cualquiera sea el tipo de ventilación utilizada, debe aplicarse con la menor presión inspiratoria y concentración de oxígeno requeridas, para mantener un adecuado intercambio gaseoso. El rango de saturación arterial de oxígeno recomendado para el niño prematuro, aún es motivo de estudio, pero la recomendación actual más ampliamente aceptada es aquella que oscila entre 88 por ciento y 95 por ciento. Conclusión: La vitamina A y la cafeína son drogas efectivas en la prevención de la DBP. Faltan estudios para determinar con mayor exactitud el posible...

Development of low cost pulmonary surfactants composed of a mixture of lipids or lipids-peptides using higher aliphatic alcohol or soy lecithin.

The artificial pulmonary surfactant composition in the present study is characterized by a lipid mixture system composed of higher aliphatic alcohol, egg yolk phosphatidylcholine (egg PC), soy lecithin and higher aliphatic acid as the major components or a peptide-lipid mixture system composed of a combination of the lipid mixture system to which a peptide is added. Three peptides with amphiphilic surface-staying, membrane spanning, and both properties were designed and synthesized. The evaluation of pulmonary surfactant assay was performed by a hysteresis curve drawn upon the measurement for the surface tension-area curve with the Wilhelmy surface tensometer in vitro and the recovery of lung compliance for the pulmonary surfactant-deficient rat models in vivo. Lipid-mixture systems composed of octadecanol or soy lecithins containing no peptide were favorable hysteresis curves as compared with commercially available Surfacten, but were not prominent. The peptide-lipid mixture systems composed of a combination of the lipid mixture of alkyl alcohol or soy lecithin to which peptides designed were added were desirable hysteresis curves similar to Surfacten and amphiphilic Hel 13-5 peptide-lipids mixture systems were much more effective than the lipid mixture system. Particularly, the recovery of lung compliance treated with hydrogenated soy lecithin-fractionated soy lecithin PC70-palmitic acid-peptide Hel 13-5 (40:40:17.5:2.5, w/w) was comparable to that with Surfacten. Because the artificial pulmonary surfactant compositions of this study can be prepared at lower costs, they are useful for the treatment of respiratory distress syndrome and acute respiratory distress syndrome as well as for inflammatory pulmonary diseases, dyspnea caused by asthma, etc.

Nonventilatory strategies for prevention and treatment of bronchopulmonary dysplasia--what is the evidence?

This review briefly summarizes the evidence for a number of mainly drug-related strategies to prevent or treat bronchopulmonary dysplasia (BPD). Oxygen supplementation is frequently used in neonatal units and oxygen toxicity plays an important role in the pathogenesis of BPD. However, current evidence for an optimal oxygen saturation for extremely premature infants is scarce. This gap in knowledge will hopefully be closed by a number of ongoing or prospective trials addressing this issue. The role of inhalational nitric oxide in the prevention of BPD is still unclear despite existing data from a number of large randomized trials. Early administration of caffeine seems to confer a benefit with regard to BPD. Prophylactic or early application of surfactant may also be beneficial. High intramuscular doses of vitamin A slightly reduce the incidence of the disease. There is currently no evidence supporting other nutritional interventions to prevent BPD. Anti-inflammatory drugs, like alpha(1)-proteinase inhibitor, pentoxifylline and azithromycin, and antioxidants, like N-acetylcysteine and superoxide dismutase, have not been proven effective yet. Diuretics can ameliorate lung function, but there is no evidence supporting their long-term use. Ureaplasma urealyticum colonization of airways is associated with an increased risk of BPD. However, there is no proof for an effect of erythromycin on BPD. The potential roles for therapies like bombesin-like peptide-blocking antibodies or Clara cell 10-kDa protein have yet to be defined.

Aerosolized lucinactant: a potential alternative to intratracheal surfactant replacement therapy.

BACKGROUND: Surfactant replacement therapy (SRT) has been demonstrated to be both safe and highly effective in the treatment of preterm infants with respiratory distress syndrome (RDS). However, administration of the various available suspensions has required endotracheal intubation and its inherent risks. Delivery of aerosolized SRT would be a laudable goal. OBJECTIVE: To review the chemistry, pharmacodynamics, clinical efficacy and safety of aerosolized lucinactant for the prevention/treatment of RDS in the preterm infant. METHODS: Laboratory and clinical experience with aerosolized lucinactant are reviewed. RESULTS/CONCLUSIONS: Laboratory studies confirm the ability of lucinactant to withstand the aerosolization process and to maintain its biological activity. A small clinical pilot trial demonstrated safety and feasibility and provided a signal to suggest proof of concept and the justification for a larger Phase III trial.

Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids.

BACKGROUND: Extensive biochemical and biophysical changes of the pulmonary surfactant system occur in the acute respiratory distress syndrome (ARDS). METHODS: The effect of intrabronchial administration of a recombinant surfactant protein C-based surfactant preparation (Venticute) on gas exchange, surfactant composition and function was investigated in 31 patients with ARDS in a randomised controlled phase I/II clinical pilot trial. Bronchoalveolar lavage fluids for surfactant analysis were obtained 3 h before and 48 and 120 h after the first surfactant application. Potentially deleterious effects of surfactant neutral lipids in patients with ARDS were also identified. RESULTS: Before treatment all patients had marked abnormalities in the surfactant phospholipid and protein composition. In response to surfactant treatment, gas exchange improved and surfactant phospholipid and protein content were almost normalised. Alveolar surface activity was dramatically impaired before treatment and only partially improved after surfactant administration. Further analysis of the bronchoalveolar lavage fluids revealed a twofold increase in neutral lipid content and altered neutral lipid profile in patients with ARDS compared with healthy controls. These differences persisted even after administration of large amounts of Venticute. Supplementation of Venticute or natural surfactant with a synthetic neutral lipid preparation, mimicking the profile in ARDS, caused a dose-dependent deterioration of surface activity in vitro. CONCLUSION: Intrabronchial surfactant treatment improves gas exchange in ARDS, but the efficacy may be limited by increased concentration and altered neutral lipid profile in surfactant under these conditions.

Neonatal outcome of triplet versus twin and singleton pregnancies: a matched case control study.

OBJECTIVE: To determine the neonatal outcome of triplet gestations versus that of singletons and twins matched for gestational age. STUDY DESIGN: All live born triplet gestations delivered between 1 April 1993 and 31 March 2000 were compared to an age matched control group consisting of live born twins and singletons. The neonatal outcome of 116 sets of triplets was compared to that of 116 sets of twins and 116 singletons. RESULTS: During a 7-year period 116 sets of triplet pregnancies were reviewed. Of 116 sets of live born triplets (348 newborns), 70.67% triplets were born between 33- and 36-week gestation, 28.44% between 28 and 32 weeks and 0.86% less than 28 weeks. Triplets were smaller in weight than singletons but not twins. Apgar score, use of prenatal steroid and sex ratio were similar in the three groups. Incidence of respiratory distress syndrome (RDS), use of surfactant, infants requiring intubation, pneumothorax, patent ductus arteriosus, sepsis, intraventricular hemorrhage, periventricular leucomalacia, retinopathy of prematurity, necrotizing enterocolitis, gastroesophageal reflux and jaundice requiring phototherapy were not statistically different among the three groups. Incidence of major and minor congenital anomalies, percent neonatal intensive care unit (NICU) admissions, and mean duration of NICU stay were also similar. There was no influence of birth order on neonatal outcome of triplet pregnancy and outcome did not significantly change over 7 years of the study period. CONCLUSIONS: Triplets have a similar outcome to twins and singletons when matched for gestational age. Since outcome is dependent on gestational age, the closer the gestational age is to term the better is the outcome.

Uso de surfactante en síndrome aspirativo meconial / Surfactant replacement therapy for meconium aspiration syndrome

El surfactante exógeno es usado de forma rutinaria para el tratamiento de recién nacidos prematuros con enfermedad de membranas hialinas y su uso en recién nacidos a término con falla respiratoria por síndrome aspirativo meconial es objeto de activa investigación. Presentamos la evolución clínica de un recién nacido a término con una falla respiratoria hipoxémica severa (Indice de oxigenación 22, gradiente alvéolo-arterial de O2 = 622 mmHg) producto de un síndrome aspirativo meconial, la que fue revertida con la administración de una dosis de surfactante exógeno. Posterior al uso de surfactante el paciente presentó una mejoría sostenida en oxigenación permitiendo una disminución rápida de la presión de la vía aeréa y una extubación a los 4 días de su ingreso

Protective effect of lung inflation in reperfusion-induced lung microvascular injury.

We used the isolated-perfused rat lung model to study the influence of pulmonary ventilation and surfactant instillation on the development of postreperfusion lung microvascular injury. We hypothesized that the state of lung inflation during ischemia contributes to the development of the injury during reperfusion. Pulmonary microvascular injury was assessed by continuously monitoring the wet lung weight and measuring the vessel wall (125)I-labeled albumin ((125)I-albumin) permeability-surface area product (PS). Sprague-Dawley rats (n = 24) were divided into one control group and five experimental groups (n = 4 rats per group). Control lungs were continuously ventilated with 20% O(2) and perfused for 120 min. All lung preparations were ventilated with 20% O(2) before the ischemia period and during the reperfusion period. The various groups differed only in the ventilatory gas mixtures used during the flow cessation: group I, ventilated with 20% O(2); group II, ventilated with 100% N(2); group III, lungs remained collapsed and unventilated; group IV, same as group III but pretreated with surfactant (4 ml/kg) instilled into the airway; and group V, same as group III but saline (4 ml/kg) was instilled into the airway. Control lungs remained isogravimetric with baseline (125)I-albumin PS value of 4.9 +/- 0.3 x 10(-3) ml x min(-1) x g wet lung wt(-1). Lung wet weight in group III increased by 1.45 +/- 0.35 g and albumin PS increased to 17.7 +/- 2.3 x 10(-3), indicating development of vascular injury during the reperfusion period. Lung wet weight and albumin PS did not increase in groups I and II, indicating that ventilation by either 20% O(2) or 100% N(2) prevented vascular injury. Pretreatment of collapsed lungs with surfactant before cessation of flow also prevented the vascular injury, whereas pretreatment with saline vehicle had no effect. These results indicate that the state of lung inflation during ischemia (irrespective of gas mixture used) and supplementation of surfactant prevent reperfusion-induced lung microvascular injury.

Dosing and delivery of a recombinant surfactant in lung-injured adult sheep.

The purpose of this study was to evaluate a surfactant based on a recombinant surfactant protein-C (rSP-C) at three different doses (25, 100, and 200 mg lipid/kg) in the saline lavage adult sheep model of acute lung injury. All three doses resulted in significant improvements in gas exchange, although the 100 and 200 mg/kg doses were superior to the 25 mg/kg dose. There were no significant differences in effect of the 100 and 200 mg/kg doses. In addition, the physiologic efficacy and lobar surfactant distribution patterns were similar when two different surfactant delivery methods were compared. This comparison involved administering the surfactant directly into each lobe under bronchoscopic guidance, versus instilling the surfactant through an endotracheal tube into the lungs. However, the former technique took significantly longer to perform (24.5 +/- 3.3 min versus 11.6 +/- 2.5 min, p < 0.05) and required a skilled bronchoscopist. In conclusion, rSP-C surfactant was effective in improving gas exchange in this model of lung injury, although higher doses were required for optimal responses. The bronchoscopic administration technique produced results similar to those of the tracheal instillation method, but had some disadvantages that may limit the widespread clinical use of this technique in patients with lung injury.

Effects of ventilation strategies on the efficacy of exogenous surfactant therapy in a rabbit model of acute lung injury.

We evaluated the effects of various ventilation strategies on the efficacy of exogenous surfactant therapy in lung-injured adult rabbits. Lung injury was induced by repetitive whole-lung saline lavage followed by mechanical ventilation. Three hours after the final lavage, 100 mg lipid/kg bovine lipid extract surfactant was instilled. After confirmation of similar responses to exogenous surfactant, animals were then randomized to one of four ventilation groups; (1) Normal tidal volume (VT) (5 cm H2O): VT = 10 ml/kg, respiratory rate (RR) = 30/min, positive end-expiratory pressure (PEEP) = 5 cm H2O; (2) Normal VT (9 cm H2O): VT = 10 ml/kg, RR = 30/min, PEEP = 9 cm H2O; (3) Low VT (5 cm H2O): VT = 5 ml/kg, RR = 60/min, PEEP = 5 cm H2O; (4) Low VT (9 cm H2O): VT = 5 ml/kg, RR = 60/min, PEEP = 9 cm H2O. Animals were ventilated for an additional 3 h and then killed, and lung lavage fluid was analyzed. Animals ventilated with the low-VT modes (Low VT [5 cm H2O] and Low VT [9 cm H2O]) had higher PaO2 values (430 +/- 7 mm Hg and 425 +/- 18 mm Hg versus 328 +/- 13 mm Hg) and higher percentages of surfactant in large aggregate forms (83 +/- 2% and 82 +/- 2% versus 67 +/- 4%) at 3 h after treatment than did the Normal VT (5 cm H2O) group (p < 0.05). Increasing the PEEP level was beneficial for a short period after surfactant administration to maintain oxygenation, but did not affect exogenous surfactant aggregate conversion. We speculate that ventilation strategies resulting in low exogenous surfactant aggregate conversion will result in superior physiologic responses to exogenous surfactant.

Effect of nitric oxide in meconium aspiration syndrome after treatment with surfactant.

OBJECTIVE: To test the hypothesis that inhaled nitric oxide may be an effective therapeutic agent in meconium aspiration syndrome and may improve oxygenation after pretreatment with surfactant. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at The Children's National Medical Center. SUBJECTS: Eight newborn pigs, 1 to 2 wks of age, 4.1 +/- 0.4 kg, were used for the study. INTERVENTIONS: Animals were anesthetized, paralyzed, intubated, and mechanically ventilated. Catheters were placed in the femoral vein and artery, and in the pulmonary artery. After 1 hr of recovery, 10 mL/kg of 20% meconium in normal saline solution was insufflated into the lungs. Animals were ventilated to maintain arterial blood gases in a normal range (i.e., pH of 7.35 to 7.45, Paco2 of 40 to 45 torr [5.3 to 6.0 kPa], and Pao2 of 70 to 90 torr [9.3 to 12.0 kPa]). Ventilatory settings were increased, as needed, until the following maximum settings were reached: FIO2 of 1.0; peak inspiratory pressure of 40 cm H2O; and intermittent mandatory ventilation of 60 breaths/min. After 2 hrs of conventional ventilation or demonstration of clinically important lung disease by failure to maintain desired blood gases on the maximum ventilatory settings, 4 mL/kg of beractant was given intratracheally. After a short period of stabilization following surfactant therapy, inhaled nitric oxide was administered. Concentrations of 40, 20, and 10 parts per million were given. To assure that there was no additive effect of inhaled nitric oxide, each dose was given for 20 mins, followed by a 15-min normalization period at 0 parts per million. MEASUREMENTS AND MAIN RESULTS: Physiologic measurements, ventilatory settings, arterial blood gases, and methemoglobin were recorded at each study period. Measurements were taken after each exposure to inhaled nitric oxide and after its discontinuation. Arterial oxygen saturation and Pao2 were significantly lower after meconium aspiration when compared with baseline values. After treatment with surfactant, administration of inhaled nitric oxide improved oxygenation without a significant decrease in pulmonary arterial pressure. CONCLUSIONS: In this model of meconium aspiration syndrome, short-term exposure to inhaled nitric oxide after treatment with surfactant improved oxygenation secondary to better distribution of inhaled nitric oxide. The increase in oxygenation may be secondary to an improved ventilation/perfusion mismatch, since the primary etiology of hypoxia in this model may be a combination of parenchymal lung disease and pulmonary hypertension.

Ultrasonic nebulization for efficient delivery of surfactant in a model of acute lung injury. Impact on gas exchange.

We investigated the effect of ultrasonic nebulization versus instillation of exogenous surfactant on gas exchange abnormalities provoked by detergent inhalation in perfused rabbit lungs. Ventilation-perfusion (VA/Q) distribution was assessed by the multiple inert gas elimination technique. For nebulization of natural bovine surfactant (Alveofact), an ultrasonic device was placed in line with the inspiratory gas flow tubing, manufacturing particles with a mass median aerodynamic diameter of approximately 4.5 microM and high aerosol concentration. In vitro studies demonstrated biochemical and biophysical integrity of postnebulization surfactant. Lung aerosol deposition was monitored by a laser-photometric technique. In lungs with sham inhalation of saline, tracheal instillation of surfactant (approximately 11 mg/kg body weight, infused over 50 min) provoked substantial VA/Q mismatch and limited shunt flow, whereas lung surfactant deposition by ultrasonic nebulization (approximately 7 to 9 mg/kg body weight; nebulization time, 50 min) did not interfere with physiologic gas exchange. Tween 20 inhalation provoked severe VA/Q mismatch with predominant shunt-flow (approximately 21%). This was not reversed by "rescue" application of instilled surfactant, but largely reversed by nebulized surfactant (shunt reduced to 5.5%; p < 0.01). Analysis of postaerosol lavage fluid demonstrated partial reconstitution of surface activity by nebulized surfactant. We conclude that ultrasonic nebulization may be employed for efficient delivery of functionally intact natural surfactant to the distal bronchoalveolar space. This approach effects rapid improvement of gas exchange in a model of acute homogeneous lung injury.

Aerosolized and instilled surfactant therapies for acute lung injury caused by intratracheal endotoxin in rats.

OBJECTIVE: To compare the effects of surfactant replacement by aerosol inhalation and bolus instillation on acute lung injury caused by the intratracheal injection of endotoxin in rats. DESIGN: Prospective, randomized study. SETTING: University Laboratory. SUBJECTS: Male Wistar rats weighing 368 +/- 31 (SD) g. INTERVENTIONS: Escherichia coli endotoxin (57 +/- 20 mg/kg) was injected into the tracheas of 36 anesthetized and mechanically ventilated rats (FIO of 1.0). When the PaO2 had decreased to <200 torr (<26.7 kPa), the rats were randomly assigned to one of three groups: a control group (n=12)given no material; a bolus group (n=12) given a modified natural surfactant suspension (100 mg/kg in 2.0 mL/kg saline) by bolus instillation into the trachea; and an aerosol group (n=12) given surfactant aerosolized with an ultra-sonic nebulizer for 60 mins. MEASUREMENTS AND MAIN RESULTS: Bolus instillation transiently decreased the mean blood pressure by approximately 30%. However, aerosol inhalation did not. The PaO2 values of the control group remained <90 torr (<12.0 kPa) until the end of the experiment (180 mins). In contrast, the PaO2 of the bolus group increased to 387 +/- 134 torr (51.6 +/- 17.9 kPa; p<.05 vs. other groups) 15 mins after surfactant replacement, and remained at approximately 400 torr (approximately 53.3 kPa) throughout the experiment. The PaO2 values of the aerosol group increased slowly, peaked at 240 +/- 109 torr (32.0 +/- 14.5 kPa; p<.05 vs. the control group) 60 mins after the start of surfactant replacement, and remained at approximately 200 torr (approximately 26.7 kPa). CONCLUSIONS: Bolus instillation was superior to aerosol inhalation concerning maximum efficacy, the rapid onset of therapeutic effects, and the necessary dose of surfactant. However, aerosol that does not cause hypotension may be of use in the treatment of adult respiratory distress syndrome in patients with circulatory instability.

Surfactant administration to the human fetus in utero: a new approach to prevention of neonatal respiratory distress syndrome (RDS).

Supplementary surfactant (80 mg in 1 ml) was administered intra-amniotically in proximity of the fetal mouth to 4 preterm fetuses (28 to 32 wks) with immature amniotic fluid indexes and whose delivery was imminent. Administration was preceded by a aminophylline infusion (loading dose of 240 mg and maintenance of 0.8 mg/kg/min) to the mother in order to elicit sustained fetal breathing movements. Following delivery by cesarean section, the absence of signs of respiratory distress in the infants along with a completely uneventful clinical course suggests that the present therapeutic approach has great potential for becoming a reliable option for the antenatal prevention of RDS.

A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. National Institute of Child Health and Human Development Neonatal Research Network.

OBJECTIVE: To compare the efficacy of two surfactants, Exosurf Neonatal (Burroughs Wellcome Co.) and Survanta (Ross Laboratories), for the treatment of neonatal respiratory distress syndrome. DESIGN: Multicenter randomized trial. SETTING: Eleven tertiary care university neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network. PATIENTS: Newborn infants (n = 617) weighing 501 to 1500 gm with respiratory distress syndrome who were receiving assisted ventilation with 30% oxygen or more within 6 hours of birth were enrolled between January 1991 and January 1992. INTERVENTIONS: Infants were randomly assigned to receive up to four intratracheal doses of either Exosurf Neonatal (n = 309) or Survanta (n = 308). MAIN OUTCOME MEASURES: The occurrence of death or bronchopulmonary dysplasia 28 days after birth and the average fraction of inspired oxygen (FIO2) and mean airway pressure (MAP) during the first 72 hours after treatment. RESULTS: Death or bronchopulmonary dysplasia occurred in 67% of the infants in the Exosurf group and 62% of those in the Survanta group (adjusted relative risk, 1.07; 95% confidence interval, 0.96 to 1.20). During the 72 hours after the first surfactant dose, the average FIO2 (+/- SEM) was 0.50 +/- 0.01 for Exosurf and 0.42 +/- 0.01 for Survanta (difference, 0.08; 95% confidence interval, 0.05 to 0.11); the average MAP (+/- SEM) was 7.64 +/- 0.21 cm H2O for Exosurf and 6.93 +/- 0.21 cm H2O for Survanta (difference, 0.71 cm H2O; 95% confidence interval, 0.13 to 1.29 cm H2O). There was no difference between the groups in the incidence of other neonatal morbidities or in the duration of hospitalization, assisted ventilation, or supplemental oxygen administration. CONCLUSION: We found no difference between treatment groups in the incidence of death or bronchopulmonary dysplasia, although we did observe a difference in the initial response to treatment as measured by FIO2 and MAP.