Treatment Of Respiratory Distress Syndrome Research Articles

Epidemiology and Risk Factors for the “New” Bronchopulmonary Dysplasia

After completing this article, readers should be able to: 1. Explain the difference in clinical course between classic bronchopulmonary dysplasia (BPD) and “new BPD.” 2. Describe the potential role of inflammation in the pathogenesis of BPD. 3. Describe how patent ductus arteriosus may affect the development of BPD. 4. Delineate the role of infection in the pathogenesis of BPD. The classic severe form of bronchopulmonary dysplasia (BPD) described by Northway and colleagues is occurring less frequently, but there is an increasing number of small preterm infants who are surviving with a milder form of chronic lung damage (Fig. 1⇓ ). These two forms of chronic lung disease (CLD) differ not only in their clinical presentation but in pathogenic mechanisms and long-term consequences. Figure 1. Incidence of BPD by birthweight among infants weighing less than 1,500 g born in 1996 through 1998 at the University of Miami/Jackson Memorial Medical Center. Classic BPD was described in infants who had severe respiratory distress syndrome (RDS) and received aggressive ventilation with high positive airway pressures and inspired oxygen concentrations. The new form of BPD occurs in smaller preterm infants, most of whom receive antenatal steroids and postnatal surfactant therapy. Because of this therapy, they experience a mild initial respiratory course and, therefore, are not exposed to aggressive ventilation or high inspired oxygen concentrations. Accordingly, the lung damage they suffer must be caused in part by other factors. Most of these infants have extremely low birthweights and require prolonged ventilator support primarily for management of apnea and poor respiratory effort. They represent more than 75% of all infants diagnosed with CLD in our institution. In contrast to infants who have severe BPD, these patients initially require low concentrations of oxygen for treatment of mild RDS that usually responds favorably to exogenous surfactant. This often is followed by a few days …

International randomised controlled trial of patient triggered ventilation in neonatal respiratory distress syndrome

AIMTo compare the effects of patient triggered ventilation (PTV) with conventional ventilation (IMV) in preterm infants ventilated for respiratory distress syndrome (RDS).METHODSNine hundred and twenty four babies from 22 neonatal...

Calfactant: a review of its use in neonatal respiratory distress syndrome.

Calfactant (Infasurt) is a natural bovine surfactant which has been evaluated for intratracheal use in the prevention and rescue treatment of respiratory distress syndrome (RDS) in preterm infants. In 2 randomised, double-blind, multicentre clinical trials of prophylactic use, calfactant 100 or 105 mg phospholipid per kg bodyweight (mg/kg) reduced RDS incidence, RDS severity and mortality rates to a greater extent than colfosceril palmitate (Exosurf Neonatal) 67.5 mg/kg and was generally similar to beractant (Survanta) 100 mg/kg. Although the rate of mortality before discharge from hospital was significantly higher in infants with birthweights <600 g who received calfactant than in those who received beractant, this may not be a typical result. As rescue treatment, calfactant 100 or 105 mg/kg reduced RDS severity, but not mortality rates, significantly more than colfosceril palmitate 67.5 mg/kg or beractant 100 mg/kg in 2 randomised, double-blind, multicentre clinical trials. In addition, the duration of effect of calfactant as prophylaxis or rescue treatment appeared to be longer than that of beractant. In other randomised trials, prophylaxis was more effective than rescue treatment with calfactant, particularly in infants of < or =29 weeks gestational age. The incidence of pulmonary air leak events was lower with calfactant than with colfosceril palmitate (12 vs 22%) but was identical with calfactant and beractant (15% with either agent). The incidence of other complications associated with RDS was usually similar with all 3 agents in clinical trials in preterm infants. The incidence of intraventricular haemorrhage was significantly higher in 1 clinical trial, and that of septicaemia was significantly lower in another, with calfactant versus colfosceril palmitate, but the combined incidences of these complications was similar with the 2 agents when results from different trials were pooled. The incidence of acute adverse events (i.e. those which occurred during administration of the drug) with calfactant was similar to that with beractant and higher than that with colfosceril palmitate; the difference may been related to reduced RDS severity in calfactant versus colfosceril palmitate recipients. Acute adverse events were usually transient and not severe. Calfactant is a well tolerated natural bovine surfactant which is effective in the prevention and treatment of RDS in preterm infants. Further investigation is needed to more clearly determine the efficacy and tolerability of calfactant relative to that of other surfactant preparations. When more data are available, it is likely that calfactant will be useful as an alternative to beractant (at least in infants of birthweights >600 g), and calfactant may be preferred over colfosceril palmitate in both the prophylaxis and treatment of RDS.

High Frequency Partial Liquid Ventilation vs. Infasurf Rescue in Preterm Lambs with Respiratory Distress Syndrome (RDS) † 1720

Surfactant replacement therapy is established as a primary treatment for RDS in preterm infants. Its efficacy however, is decreased in advanced disease states. Partial liquid ventilation (PLV) with perflubron (LiquiVentr) appears to improve lung function in infants with RDS who have failed to respond to exogenous surfactant. We hypothesized that PLV alone would improve lung function as compared with exogenous surfactant (Infasurfr) in the rescue treatment of severe RDS. We studied preterm lambs delivered by C-section(gest. age 125-127 days) with severe advanced RDS (criteria: PaO2 20-40 mmHg at 3 hours of life). Lambs were placed on high frequency ventilation (Sensormedics 3100A) with F1O2 1.0, amplitude 50 cmH2O, frequency 8-10 Hz, and mean airway pressure 15 cmH2O. At 3 h, animals received either Infasurf (100 mg/kg) or PLV with LiquiVent (25 ml/kg initial dose with replacement of evaporative losses).Results: PaO2 was increased 2.5-fold within 30 minutes in the LiquiVent group, and this improvement was sustained for the two hours of study. In contrast, the Infasurf group showed minimal response in PaO2, and this value returned to pretreatment baseline by 2 hours. PaCO2 trended downward with PLV (PaCO2: 70± 10 mmHg to 54 ± 7 mmHg) as compared with Infasurf(PaCO2: 69 ± 7 mmHg to 65 ± 8 mmHg). Necropsy revealed hemorrhagic, edematous lungs in the Infasurf group and less diffuse and less severe changes in the LiquiVent group. We conclude that PLV with LiquiVent is more effective than Infasurf in the treatment of severe, advanced RDS in the preterm lamb. PLV may be useful as a primary intervention in infants with severe advanced RDS. Figure

Lung function in premature rabbits treated with recombinant human surfactant protein-C.

We report the activity of recombinant human surfactant apoprotein-C (rSP-C[Cys]2) and various phospholipids in a preterm rabbit model of respiratory distress syndrome (RDS). Mixtures of rSP-C(Cys)2 and certain phospholipids had similar activity (lung compliance and lung pressure-volume behavior) to rabbit surfactant in this model. The activity of rSP-C(Cys)2 was maximal at 1 mol% protein and varied significantly with the phospholipid composition. Chemically synthesized SP-C had similar activity to rSP-C(Cys)2. Deletion of six amino-terminal residues did not affect function. Substitution of cysteines and cysteine6 with adjacent serines (rSP-C[Ser]2) by site-specific mutagenesis minimized aggregation of rSP-C but did not affect activity. Palmitoylation of cysteine5 and cysteine6 in rSP-C (rSP-C[C16]2) did not enhance the activity of rSP-C(Cys)2. We conclude that bacterial expression is a practical source of functional SP-C, and that nonacylated forms of SP-C may be useful adjuvants to phospholipids in the treatment of RDS and possibly other forms of acute lung injury.

Surfactant aerosol treatment of respiratory distress syndrome in the spontaneously breathing premature rabbit.

Surfactant deficiency in premature neonates is a major factor in the development of respiratory distress syndrome (RDS), which is still a significant cause of mortality and morbidity. The aim of this study was to test a noninvasive method of administering surfactant as treatment for RDS. The animal model used was the premature neonatal rabbit of 27-d gestation (full-term being 31 d) primed with an initial oropharyngeal dose of surfactant. The animals were divided into three groups that received either no supplemental surfactant (n = 20), undried nebulized surfactant (n = 21), or dried nebulized surfactant (n = 24). Drying of the surfactant solution was undertaken to create a hygroscopic aerosol that would facilitate surfactant deposition in the lower respiratory tract. The group treated with dried surfactant aerosol showed superior survival (66.7%) and less evidence of RDS. The control and undried aerosol groups each had similar low survival rates (23.8 and 45.0%, respectively). The results indicate that a dried, hygroscopic aerosol is an effective means of administration of surfactant to spontaneously breathing premature rabbit neonates.

Respiratory distress syndrome of the newborn infant.

Pulmonary immaturity, including deficiency in the surfactant system, incomplete structural/functional development of lungs and high chest wall compliance contribute to the pathogenesis of respiratory distress syndrome (RDS). Pulmonary edema and overperfusion, resulting from a patent ductus arteriosus, may further worsen the respiratory failure, and aggravate the surfactant deficiency. Infants born prematurely present with respiratory distress within the first few minutes of life. This quickly becomes life-threatening, and may result in death from severe respiratory failure if appropriate respiratory and general supportive therapy are not immediately instituted. The oxygenation deficit in RDS is secondary to V/Q mismatch and right-left shunting of blood via pulmonary and extrapulmonary routes. Hypoxemia induced pulmonary vasoconstriction further contributes to V/Q mismatch and R-L shunting. Hypoventilation in RDS is due to decreased tidal volume, increased dead space ventilation, and finally, decreased minute ventilation. Characteristically, pulmonary compliance, both static and dynamic, are greatly reduced resulting in a high work of breathing, whereas airway resistance is normal or only slightly increased. This combination of abnormal pulmonary mechanics results in lower respiratory time constant in respiratory units, and helps in achieving ventilation and oxygenation by using low inspiratory time in the ventilator. Management of RDS starts with prenatal identification of the risk, prolongation of pregnancy by tocolysis and prenatal administration of pharmacological agents, like betamethasone. These agents increase the pulmonary gas exchange surface area and induce endogenous pulmonary surfactant in the fetus. Advances in ventilatory and general management techniques have strikingly improved the outcome and prognosis of children suffering from RDS since the 1960s. Recent advancements in the prevention and treatment of RDS, e.g., acceleration of lung development by prenatal pharmacological manipulations and postnatal provision of exogenous surfactant, have significantly contributed to the decrease in mortality from RDS. Pharmacological induction of lung maturation by drugs in combination, and improved technology in lung ventilation are expected to further improve the course and outcome of the disease in future.

Partial liquid ventilation in premature lambs with respiratory distress syndrome: Efficacy and compatibility with exogenous surfactant

Objective: To determine the efficacy of partial liquid ventilation (PLV) by means of a medical-grade perfluorochemical liquid, perflubron (LiquiVent), in premature lambs with respiratory distress syndrome (RDS). Further, to determine the compatibility of perflubron with exogenous surfactant both in vitro and in vivo during PLV. Design: Prospective, randomized, controlled study, with in vitro open comparison. Subjects: Twenty-two premature lambs with RDS. Interventions: In vitro assays were conducted on three exogenous surfactants before and after combination with perflubron. We studied four groups of lambs, which received one of the following treatment strategies: conventional mechanical ventilation (CMV); surfactant (Exosurf) plus CMV; PLV; or surfactant plus PLV. Measurements and main results: In vitro surface tension, measured for three exogenous surfactants, was unchanged in each animal after exposure to perflubron. Lung mechanics and arterial blood gases were serially measured. All animals treated with PLV survived the 5 hours of experiment without complication; several animals treated with CMV died. During CMV, all animals had marked hypoxemia and hypercapnia. During PLV, arterial oxygen tension increased sixfold to sevenfold within minutes of initiation, and this increase was sustained; arterial carbon dioxide tension decreased to within the normal range. Compliance increased fourfold to fivefold during PLV compared with CMV. Tidal volumes were increased during PLV, with lower mean airway pressure. Resistance was similar for both CMV and PLV; there was no difference with surfactant treatment. Conclusions: We conclude that PLV with perflubron improves lung mechanics and gas exchange in premature lambs with RDS, that PLV is compatible with exogenous surfactant therapy, and that, as a treatment for RDS in this model, PLV is superior to the surfactant studied. (J P EDIATR 1995;126:412-20)

Clinical Trials of Natural Surfactant Extract in Respiratory Distress Syndrome

Since the first use of natural surfactant extract by Fujiwara to treat premature infants with respiratory distress syndrome (RDS), multiple randomized controlled clinical trials involving more than 2500 infants have been reported. These trials have used prophylactic administration of surfactant to high-risk premature infants (prevention trials) or administration of surfactant to premature infants with moderate to severe RDS (rescue or treatment trials). This article shows meta-analysis of the trial data, significant effects of natural surfactant extracts, and significant clinical benefits.

Early versus delayed neonatal administration of a synthetic surfactant — The judgment of OSIRIS

Although exogenous surfactants are of known efficacy in the prevention and treatment of respiratory distress syndrome (RDS), questions remain about the best regimens. During 1990-91, 6774 babies were recruited to an international multicentre trial to assess when administration of Exosurf, a synthetic surfactant should be started and how often it should be given. The clinical outcome is known for 6757 (99.7%) infants. 2690 babies, judged to be at high risk of RDS when less than 2 hours of age, were randomly allocated to either early administration or delayed selective administration; 96% versus 73% received surfactant, at median ages of 118 and 182 min. The risk of death or dependence on extra oxygen at the expected date of delivery was 16% (95% Cl 25% to 7%) lower among infants allocated early administration. Early administration was also associated with a 32% lower risk of pneumothorax. These 2690 infants were further randomised in a factorial design to either two doses of surfactant 12 hours apart, or the option of third and fourth doses at 12-36 hour intervals if signs of RDS persisted or recurred. 4067 other infants who later developed RDS were also recruited to this comparison, giving a total of 3376 infants allocated up-to-four doses (of whom, 45% received more than two) and 3381 allocated two doses. The outcome was similar in the two groups in respect of death, long-term oxygen dependence, and other major morbidity, even in secondary analyses restricted to infants who met the criteria for additional administration. There were more reports of poorly tolerated administration in the up-to-four doses group but no clear increase in serious morbidity, such as pulmonary haemorrhage. The OSIRIS trial suggests that early administration of surfactant to an estimated 32 babies, when compared with treatment of established RDS, would prevent 1 baby from dying and another from being dependent on extra oxygen long-term, but would entail the additional use of surfactant in 8 of these babies. It provides no evidence that a regimen including the option of third and fourth doses when signs of RDS persist or recur is clinically superior to a regimen of two doses.

Cost effectiveness of surfactant replacement in preterm babies.

Surfactant replacement in preterm babies has been shown in recent years in randomised controlled trials to be an effective treatment for respiratory distress syndrome (RDS). It is expensive and, because it increases survival, it has implications for the costs of neonatal services. We used evidence about resource use obtained from trials of surfactant and other studies on the economics of surfactant to assess the cost effectiveness of different policies for its use. For the smallest babies, surfactant is likely to increase overall costs of neonatal care, but also to reduce the ratio of costs to survival, whether surfactant is given prophylactically or as a treatment for established RDS. It is less clear what the optimal policy should be for babies of more than around 31 weeks' gestation. Comparison of the relative cost effectiveness of policies of early prophylactic surfactant and surfactant for later treatment of RDS, and of different dosage policies, is currently being conducted in the context of 2 large multicentre trials. No policy for surfactant use should be considered in isolation from the availability of effective obstetric interventions which have been shown to reduce the risk of RDS in preterm babies and which will therefore reduce the need for surfactant.

Early versus delayed neonatal administration of a synthetic surfactant — the judgment of OSIRIS

Although exogenous surfactants are of known efficacy in the prevention and treatment of respiratory distress syndrome (RDS), questions remain about the best regimens. During 1990-91, 6774 babies were recruited to an international multicentre trial to assess when administration of Exosurf, a synthetic surfactant, should be started and how often it should be given. The clinical outcome is known for 6757 (99·7%) infants. 2690 babies, judged to be at high risk of RDS when less than 2 hours of age, were randomly allocated to either early administration or delayed selective administration; 96% versus 73% received surfactant, at median ages of 118 and 182 min. The risk of death or dependence on extra oxygen at the expected date of delivery was 16% (95% Cl 25% to 7%) lower among infants allocated early administration. Early administration was also associated with a 32% lower risk of pneumothorax. These 2690 infants were further randomised in a factorial design to either two doses of surfactant 12 hours apart, or the option of third and fourth doses at 12-36 hour intervals if signs of RDS persisted or recurred. 4067 other infants who later developed RDS were also recruited to this comparison, giving a total of 3376 infants allocated up-to-four doses (of whom, 45% received more than two) and 3381 allocated two doses. The outcome was similar in the two groups in respect of death, long-term oxygen dependence, and other major morbidity, even in secondary analyses restricted to infants who met the criteria for additional administration. There were more reports of poorly tolerated administration in the up-to-four doses group but no clear increase in serious morbidity, such as pulmonary haemorrhage. The OSI RIS trial suggests that early administration of surfactant to an estimated 32 babies, when compared with treatment of established RDS, would prevent 1 baby from dying and another from being dependent on extra oxygen long-term, but would entail the additional use of surfactant in 8 of these babies. It provides no evidence that a regimen including the option of third and fourth doses when signs of RDS persist or recur is clinically superior to a regimen of two doses.

Flow-immunofluorescent studies of lung surfactant protein (SP-B)

Respiratory distress syndrome (RDS), a life threatening disorder, occurs if a lipid-protein complex which lines the airspaces of the lungs is compromised. Successful treatment of RDS has been reported with a vesicular dispersion containing dipalmitoylphosphatidylcholine (DPPC), egg phosphatidylglycerol (egg PG), palmitic acid and lung surfactant protein, SP-B. It has been hypothesized that amphipathic regions of SP-B are important in these synthetic lung surfactants as they serve as a point of insertion for the protein into the lipid bilayer. Therefore two amphipathic peptides, SP-B(l-25) and SP-B(49-66), were synthesized to use in reconstitution studies. The incorporation of SP-B(l-25) into lipid bilayer has been visualized using immunofluorescent tagging in a specially designed flow-chamber.

Preterm Factors Influencing Surfactant Deficiency

Surfactant deficiency has come to be understood as equivalent clinically to lung immaturity, except in situations of extreme prematurity or lung hypoplasia. Thus, surfactant deficiency and the diagnosis respiratory distress syndrome (RDS) have been applied quite uniformly to preterm infants with respiratory distress who have no other identifiable problems. While the diagnosis can be made more specific by assay of surfactant phospholipid composition (12), such measurements are seldom made in clinical practice. Perinatal discussions of the premature with respiratory distress also have been focused toward surfactant by the availability of multiple tests of “lung maturation” based on the assay of surfactant components in amniotic fluid (19). While surfactant is necessary for normal lung function, adequate surfactant is not sufficient to assure normal gas exchange in the preterm. There are no simple ways to separate surfactant deficiency states clearly from other aspects of lung development, such as airway development, alveolarization, and the development of the pulmonary vasculature in the preterm infant. The anatomic data of Hislop et al. (13) and Langston et al. (22) indicate a considerable variability in the number of alveoli in the preterm infant at each gestational age, resulting in large differences in potential gas exchange surfaces in different infants. Airway development also differs between infants of comparable gestational ages, as is evident clinically by susceptibility to the development of pulmonary interstitial emphysema. Assuming that surfactant treatments for RDS fully correct the surfactant deficiency, a realistic expectation based on animal studies (16), surfactant treatments should be useful in the near future to eliminate the surfactant deficiency component of lung immaturity syndromes. Any residual lung disease can then be better characterized.

Respiratory distress syndrome in very low birth weigh infants with occasionally normal surfactant phospholipids.

Lung effluent phospholipids were analysed in 120 very lwo birth weight (560–1500g) infants within 12 h from birth. The phospholipid profile accurately predicted the presence or absence of respiratory distress syndrome (RDS). However, in three of the 72 RDS cases, the phospholipids revealed no biochemical abnormality as compared to lung effluent from newborns without RDS. In RDS with normal phospholipids, only the lipid-rich fractions of the aspirate were surface active, whereas the protein-rich fraction of the aspirate inhibited the surface activity of lung effluent from normal newborns, suggesting the presence of a surfactant inhibitor. The pathogenesis and treatment of RDS with normal surfactant phospholipids may prove to be different from “classical” RDS.

INTRAVENTRICULAR HAEMORRHAGE IN THE NEWBORN

Coagulation studies were performed on 128 babies who were premature or who had respiratory distress syndrome (RDS). Forty-four babies were found to have abnormal coagulation parameters. Twenty-one were treated with plasma coagulation factors II, VII, IX and X (PPSB), and of these six died from intraventricular haemorrhage (IVH). Twenty-two did not have PPSB treatment and four died from IVH. In 84 babies in whom coagulation studies gave normal results only one baby died from IVH. The combination of RDS and abnormal coagulation produced a high-risk group to IVH and treatment with PPSB did not reduce the incidence of IVH. It is postulated that prevention of IVH lies in early and effective treatment of RDS.

INTRAVENTRICULAR HAEMORRHAGE IN THE NEWBORN

Coagulation studies were performed on 128 babies who were premature or who had respiratory distress syndrome (RDS). Forty-four babies were found to have abnormal coagulation parameters. Twenty-one were treated with plasma coagulation factors II, VII, IX and X (PPSB), and of these six died from intraventricular haemorrhage (IVH). Twenty-two did not have PPSB treatment and four died from IVH. In 84 babies in whom coagulation studies gave normal results only one baby died from IVH. The combination of RDS and abnormal coagulation produced a high-risk group to IVH and treatment with PPSB did not reduce the incidence of IVH. It is postulated that prevention of IVH lies in early and effective treatment of RDS.

Die Peritonealdialyse zur Behandlung reifer und unreifer Neugeborener mit Atemnosyndrom

Some authors have recommended peritoneal dialysis to improve the therapy of the respiratory distress syndrome (RDS) of newborns. In 1968 we published a report estimated on a newborn suffering from RDS. As a pH of 6.73, was 2 hrs after birth, we administered standard therapy and peritoneal dialysis. The baby has survived and his development has been uneventful.This case and the results obtained by other authors in the treatment of RDS with peritoneal dialysis have led us to treat prematures and newborns suffering from severe RDS with peritoneal dialysis in addition to standard therapy (infusions of THAM, glucose, electrolytes, amino acids, administration of antibiotics and oxygen, and, when indicated, intermittent positive-pressure respiration). Peritoneal dialysis was carried out with bland hypertonic solution in continuous flow technics.We have treated 13 prematures and 1 newborn suffering from RDS and a premature suffering from erythroblastosis with hydrops and RDS. Except for the mature newborn, the gestational age was 25 to 33 weeks. Four prematures had birth weights below 1250 g. The Apgar score of 10 newborns was 3 or less 1 min after birth. Thirteen newborn needed resuscitation in the delivery room. Eight newborns were treated with respiration during the first few hours after birth and 4 other prematures at a later stage. Clinical and laboratory data after birth, on admission to the pediatric hospital and during the course of the disease are shown in tables and figures. The indications for the peritoneal dialysis are described in tables. In 2 patients we saw no positive effect, and we saw only a slight effect in 4 patients. Four prematures survived. The physical and psychological development was normal in 3 infants. One premature with a birth weight of 1200 g had recovered before she died of Candida sepsis at the age of 26 days.Results of the treatment and the efficacy and technical problems of peritoneal dialysis in RDS of newborns are discussed. Our opinion is that the peritoneal dialysis is a good additional aid in the treatment of RDS of prematures and newborns.

Meteorism during Treatment of Respiratory-Distress Syndrome by Intermittent Positive-Pressure Ventilation

Meteorism during Treatment of Respiratory-Distress Syndrome by Intermittent Positive-Pressure Ventilation