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Surfactant replacement therapy for severe neonatal respiratory distress syndrome: An international randomized clinical trial
Abstract
In a randomized multicenter trial, involving the collaboration of eight European neonatal intensive care units, the efficacy of replacement therapy with a new surfactant preparation (Curosurf) was tested in 146 patients with severe neonatal respiratory distress syndrome. Criteria for entry included birth weight 700 to 2,000 g, age when treated two to 15 hours, and requirement of artificial ventilation with FiO2 ≥ 0.6. The babies were treated with a single large dose of surfactant (200 mg/kg) at a median age of nine hours (range two to 15 hours). Average FiO2 before treatment was the same (0.80) for both surfactant-treated patients and control patients. Babies receiving surfactant showed, within five minutes, a dramatic improvement of oxygenation as reflected by a nearly threefold increase of PaO2/FiO2 ratio. Six hours after randomization, the PaO2/FiO2 ratio still showed a 98% improvement in surfactant-treated patients compared with controls (P < .001), and statistically significant differences in favor of the treated babies persisted until 48 hours after randomization, when surviving control infants began to recover. Treatment with surfactant decreased neonatal (≤28 days) mortality from 51% to 31% (P < .05). Compared with control babies, the surfactant-treated group also had a decreased incidence of pulmonary interstitial emphysema (23% v 39%; P < .05) and pneumothorax (18% v 35%; P < .05). The percentage of survivors without bronchopulmonary dysplasia in the treated group was more than twice that of the control group (55% v 26%; P < .001). Treatment with this surfactant appears to effectively improve lung function and short-term outcome in infants with severe respiratory distress syndrome.
... The results of the first RCT using a natural porcine surfactant to treat severe RDS were published in 1988, convincingly demonstrating a reduction in air leak, death, and the combined outcome of death or BPD [34]. Additional trials helped to fine-tune surfactant therapy in the management of RDS and revealed a key thematic link between treatment and outcome: the earlier RDS was accurately diagnosed and appropriately treated with surfactant, the better the outcome. ...
... In 2021, preterm infants at highest risk of RDS and later BPD differ significantly from subjects enrolled in the surfactant trials in the 1980s and early 1990s. While the Collaborative European Multicenter Study Group had enrolled subjects averaging 28.5 weeks of gestation [34], data from the NICHD Neonatal Research Network centers revealed increased survival from 1993 to 2012 in those born at 23, 24, 25, and 27 weeks of gestation [17]. In this same population, rates of BPD were about 40-90% [17], indicating that the most vulnerable babies are surviving at rates higher than ever before, but with significant morbidities. ...
Within the last decades, therapeutic advances have significantly improved the survival of extremely preterm infants. In contrast, the incidence of major neonatal morbidities, including bronchopulmonary dysplasia, has not declined. Given the well-established relationship between exposure to invasive mechanical ventilation and neonatal lung injury, neonatologists have sought for effective strategies of noninvasive respiratory support in high-risk infants. Continuous positive airway pressure has replaced invasive mechanical ventilation for the initial stabilization and the treatment of respiratory distress syndrome. Today, noninvasive respiratory support has been adopted even in the tiniest babies with the highest risk of lung injury. Moreover, different modes of noninvasive respiratory support supplemented by a number of adjunctive measures and rescue strategies have entered clinical practice with the goal of preventing intubation or reintubation. However, does this unquestionably important paradigm shift to strategies focused on noninvasive support lull us into a false sense of security? Can we do better in (i) identifying those very immature preterm infants best equipped for noninvasive stabilization, can we improve (ii) determinants of failure of noninvasive respiratory support in the individual infant and underlying etiology, and can we enhance (iii) success of noninvasive respiratory support and (iv) better prevent ultimate harm to the developing lung? With increased survival of infants at the highest risk of developing lung injury and an unchanging burden of bronchopulmonary dysplasia, we should question indiscriminate use of noninvasive respiratory support and address the above issues.
... The infants enrolled in these trials were more mature. For example, the babies enrolled in the surfactant replacement therapy for severe RDS by the Collaborative European Multicenter Study Group were on average 28.5 weeks' gestation (28). ACS exposure was not reported (28). ...
... For example, the babies enrolled in the surfactant replacement therapy for severe RDS by the Collaborative European Multicenter Study Group were on average 28.5 weeks' gestation (28). ACS exposure was not reported (28). Meta-analyses revealed that babies enrolled in RCTs evaluating the use of prophylactic surfactant were ∼27 weeks of gestational age (GA), and ACS exposure was low (∼30-40%) (25). ...
Within the last decades, therapeutic advances, such as antenatal corticosteroids, surfactant replacement, monitored administration of supplemental oxygen, and sophisticated ventilatory support have significantly improved the survival of extremely premature infants. In contrast, the incidence of some neonatal morbidities has not declined. Rates of bronchopulmonary dysplasia (BPD) remain high and have prompted neonatologists to seek effective strategies of non-invasive respiratory support in high risk infants in order to avoid harmful effects associated with invasive mechanical ventilation. There has been a stepwise replacement of invasive mechanical ventilation by early continuous positive airway pressure (CPAP) as the preferred strategy for initial stabilization and for early respiratory support of the premature infant and management of respiratory distress syndrome. However, the vast majority of high risk babies are mechanically ventilated at least once during their NICU stay. Adjunctive therapies aiming at the prevention of CPAP failure and the support of functional residual capacity have been introduced into clinical practice, including alternative techniques of administering surfactant as well as non-invasive ventilation approaches. In contrast, the strategy of applying sustained lung inflations in the delivery room has recently been abandoned due to evidence of higher rates of death within the first 48 h of life.
... In this study all mothers treated with PNC received only a single course (complete or incomplete) of PNC. Surfactant -Exogenous surfactant therapy to prevent or to treat HMD in premature infants clearly reduced neonatal mortality and survival without BPD 27 . Although some studies show that treatment with exogenous surfactant may decrease the incidence or severity of BPD, the fact is that surfactant use has not clearly reduced the incidence of BPD 28 . ...
... Surfactant dysfunction resulting from these events may also contribute to the pathogenesis of BPD, justifying exogenous surfactant treatment to decrease inflammation and improve RDS 29 . Nowadays exogenous surfactant is used worldwide in neonatal intensive care [27][28][29][30][31][32][33][34] . ...
With the advent of surfactant, prenatal corticosteroids (PNC) and advances in technology, the survival rate of extremely low birth weight (ELBW) infants has improved dramatically. Rates of bronchopulmonary dysplasia (BPD) vary widely among neonatal intensive care units (NICUs) and many studies using multiple interventions have shown some improvement in BPD rates. Implementing potentially better practices to reduce BPD has been an effort made over the last few decades. Aim: To compare five Portuguese NICUs in terms of clinical practices in very low birth weight (VLBW) infants, in order to developbetter practices to prevent BPD. Patients and methods: 256 preterm neonates, gestational age (GA)
... Recently, changes in the profile and survival rates of PTIs, especially those with very low birth weights, have led to modifications in the antenatal and postnatal care provided to them 1,4,5 . With regard to postnatal care, exogenous surfactant therapy 6,7 and developmental care centered on the newborns (NBs) and their families 8,9 are of particular relevance. ...
... Exogenous surfactant replacement therapy significantly improves oxygenation, which can reduce time on mechanical ventilation (MV), oxygen use, length of hospital stay, and the mortality rate among PTIs 6,7 . However, evidence shows that this therapy is associated with adverse events such as acute episodes of decreased peripheral oxygen saturation, bradycardia, pulmonary hemorrhage, and systemic hypotension, all of which can lead to changes in cerebral blood flow and the risk of periintraventricular hemorrhage (PIVH) 10 . ...
BACKGROUND:
The practice of minimal handling is recommended for preterm infants (PTIs). However, few studies have investigated the effects of this practice among these infants or the time needed to ensure greater physiological stability, especially after exogenous surfactant treatments.
OBJECTIVE:
The current study compared the effects of two protocols of minimal handling on the physiological variables of PTIs after surfactant therapy.
METHOD
: An exploratory prospective observational study was performed with 40 PTIs weighing less than 1,500 g. The infants were divided into two groups and monitored for 72 hours. One group received the standard minimal handling procedure during the first 12 hours after surfactant therapy; the other group (i.e., the modified group) received minimal handling within 72 hours after surfactant therapy. Infant heart rate (HR), oxygen saturation, body temperature, and the adverse events associated with changes to these variables were monitored every 10 minutes.
RESULTS
: Significant between-group differences were not found with regard to the occurrence of the adverse events associated with physiological changes (p>0.05).
CONCLUSION:
The practice of minimal handling among very low birth weight infants did not alter their physiological stability when performed either 12 or 72 hours after surfactant therapy.
... 65 However, persistent or permanent airway closure may exist as a result of decreased structural stiffness of the airways, 66 increased volume of fluid in the lungs, 67 or increased surface tension of the liquid lining. 68 Deliberate medical interventions 69 and some other factors such as sleep, anesthesia, and obesity 70,71 also contribute to the occurrence of airway closure. ...
The outbreak of the coronavirus disease has drawn public attention to the transmission of infectious pathogens, and as major carriers of those pathogens, respiratory droplets play an important role in the process of transmission. This Review describes respiratory droplets from a physical and mechanical perspective, especially their correlation with the transmission of infectious pathogens. It covers the important aspects of (i) the generation and expulsion of droplets during respiratory activities, (ii) the transport and evolution of respiratory droplets in the ambient environment, and (iii) the inhalation and deposition of droplets in the human respiratory tract. State-of-the-art experimental, computational, and theoretical models and results are presented, and the corresponding knowledge gaps are identified. This Review stresses the multidisciplinary nature of its subject and appeals for collaboration among different fields to fight the present pandemic.
... We found significant reductions in pulmonary air leaks, neonatal mortality and death or bronchopulmonary dysplasia (BPD) in treated infants. 21 Subsequent trials studied single versus multiple doses, early versus late surfactant treatment, use of CPAP and surfactant and comparisons with other surfactant preparations. 22,23 For the first few studies in the 1980s and 1990s mortality fell from 50% in controls to 30% with single dose treatment to about 10% with multiple doses, but remember this was late rescue treatment more than 30 years ago, a far cry from today's practice. ...
... As this was the 30th Anniversary of the first International Surfactant Workshop held in Amsterdam in 1986, Tore Curstedt from Stockholm described the history of the development of Curosurf and the first treatment of a preterm infant with this surfactant in the 1980s [1,3] . Henry Halliday from Belfast spoke about the first randomized controlled trial of Curosurf which began early in 1985 [4] and was the first to show that surfactant treatment could reduce neonatal mortality. He also reviewed mechanical ventilation and oxygen therapy after preterm birth. ...
This Preface has no abstract. The paper introduces the 30th International Workshop on Surfactant Replacement held in Stockholm in June 2015.
... Strong evidence demonstrated the efficacy of surfactant in the prevention and treatment of RDS with improved survival in very premature infants. [14][15][16] Over the last few decades, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) have reported trends in the morbidity and mortality among very low birth weight (VLBW) infants, demonstrating that increased improvements in prenatal, obstetric, and neonatal care have translated to increased survival. [2,3] However, recent evidence suggests that a plateau has occurred and there has been no significant increase in survival rates of VLBW infants without long-term morbidity. ...
Extremely low gestational age newborns (ELGANs), born at less than 28 weeks' estimated gestational age, suffer the greatest consequences of prematurity. There have been significant advances in their care over the last several decades, but the prospects for major advances within traditional treatment modalities appear limited. An artificial placenta using extracorporeal life support (ECLS) has been investigated in the laboratory as a new advance in the treatment of ELGANs. We review the concept of an artificial placenta, the purported benefits, and the most recent research efforts in this area.
For 50 years, researchers have attempted to develop an artificial placenta based on ECLS. Traditional artificial placenta strategies have been based on arteriovenous ECLS using the umbilical vessels with moderate success. Recently, the use of venovenous ECLS and miniaturization of ECLS components have shown potential for creating a next-generation artificial placenta.
ELGANs suffer the greatest morbidity and mortality of prematurity, and are poised to benefit from a paradigm shift in the treatment. Although challenges remain, the artificial placenta is feasible. An artificial placenta would not only protect ELGANs from the complications of mechanical ventilation, but also support their development until a stage of greater maturity, preparing them for a life free of the sequelae of prematurity.
... However, ECMO use to treat severe neonatal respiratory failure peaked in 1992 and steadily declined since, as advances in other less invasive therapies occurred [11,12] such as high frequency oscillatory ventilation [13][14][15] , inhaled nitric oxide [15][16][17][18][19][20] , surfactant [21,22] and maternal antibiotic therapy [23,24] . In 2011, neonatal respiratory failure accounted for 24% of cases reported to ELSO. ...
Extracorporeal membrane oxygenation (ECMO) is currently used to support patients of all ages with acute severe respiratory failure non-responsive to conventional treatments, and although initial use was almost exclusively in neonates, use for this age group is decreasing while use in older children remains stable (300-500 cases annually) and support for adults is increasing. Recent advances in technology include: refinement of double lumen veno-venous (VV) cannulas to support a large range of patient size, pumps with lower prime volumes, more efficient oxygenators, changes in circuit configuration to decrease turbulent flow and hemolysis. Veno-arterial (VA) mode of support remains the predominant type used; however, VV support has lower risk of central nervous injury and mortality. Key to successful survival is implementation of ECMO before irreversible organ injury develops, unless support with ECMO is used as a bridge to transplant. Among pediatric patients treated with ECMO mortality varies by pulmonary diagnosis, underlying condition, other non-pulmonary organ dysfunction as well as patient age, but has remained relatively unchanged overall (43%) over the past several decades. Additional risk factors associated with death include prolonged use of mechanical ventilation (> 2 wk) prior to ECMO, use of VA ECMO, older patient age, prolonged ECMO support as well as complications during ECMO. Medical evidence regarding daily patient management specifically related to ECMO is scant, it usually mirrors care recommended for similar patients treated without ECMO. Linkage of the Extracorporeal Life Support Organization dataset with other databases and collaborative research networks will be required to address this knowledge deficit as most centers treat only a few pediatric respiratory failure patients each year.
... Numerosos estudios confirman la efectividad del surfactante, que mejora la función pulmonar, disminuye la necesidad de oxígeno y ventilación mecánica (VM), y las tasas de neumotórax, enfermedad pulmonar crónica (EPC) y mortalidad [8][9][10][11] . Existen también pruebas experimentales y clínicas del beneficio del uso combinado de ambas estrategias 12,13 . ...
Objective
To determine clinical practice variability in the prevention and postnatal treatment of lung immaturity in Spain
Patients and methods
Cross-sectional study within a larger study in 13 European countries. Data were obtained from the medical records of all very low birth weight (VLBW) infants born in participating centers, without other instrumentation.
Results
A questionnaire was sent to 213 centers. Seventy-two (34 %) responded, with 162,157 births (40 % of total births in 1999). Eight percent of infants were of low birth weight, 1.2% (2,015) of very low birth weight and 0.45 % were of extremely low birth weight. A total of 52.2% of VLBW infants received at least one dose of prenatal steroids, 28.8% received a full course and 9.3 % received more than one cycle. All centres used surfactant and 76.8 % had a written protocol. Forty-one percent of VLBW infants were intubated, 47.6% required mechanical ventilation for more than 6 hours, and 5% underwent continuous positive airway pressure. A total of 80.4 % used postnatal steroids, half of them for chronic lung disease prevention, and 83.4 % used steroids to treat this disease. Steroids were most frequently indicated at 7-14 days of life for 3-9 days. The most important causes of neonatal morbidity were chronic lung disease in 14 %, ductus arteriosus in 16.7 %, intraventricular hemorrhage in 8.5 %, and necrotizing enterocolitis in 7.3%.
Conclusions
Prenatal exposure to steroids was low. Repeat cycles and postnatal steroid use to prevent chronic lung disease was high. Recent scientific evidence on the use of pre- and postnatal steroids should be more widely disseminated.
... Two main categories of surfactant preparations have been described: those containing only synthetic components and those extracted from natural sources with organic solvents, with or without subsequent modification by the addition of lipids and surfactant associated proteins (Robertson & Halliday 1998). Several different preparations with differing compositions are currently being used in clinical trials around the world (Robertson 1988, Robertson et al. 1992, Fujiwara et al. 1990, Spragg 1998, Soll 1998). ...
An exogenous natural lung surfactant obtained from minced pig lungs can be produced by a technology using a low cost, DEAE-cellulose adsorbent. This surfactant is composed mainly with phospholipids and the two hydrophobic polypeptides, SP-B and SP-C, both of which are necessary for optimal function of surfactants used for treatment of respiratory distress syndrome.
Importance:
Although preterm birth is associated with later deficits in lung function, there is a paucity of information on geographical differences and whether improvements occur over time, especially after surfactant was introduced.
Objective:
To determine deficits in percentage predicted forced expiratory volume in 1 second (%FEV1) in preterm-born study participants, including those with bronchopulmonary dysplasia (BPD) in infancy, when compared with term-born control groups.
Data sources:
Eight databases searched up to December 2021.
Study selection:
Studies reporting spirometry for preterm-born participants with or without a term-born control group were identified.
Data extraction and synthesis:
Data were extracted and quality assessed by 1 reviewer and checked by another. Data were pooled using random-effects models and analyzed using Review Manager and the R metafor package.
Main outcomes and measures:
Deficits in %FEV1 between preterm-born and term groups. Associations between deficits in %FEV1 and year of birth, age, introduction of surfactant therapy, and geographical region of birth and residence were also assessed.
Results:
From 16 856 titles, 685 full articles were screened: 86 with and without term-born control groups were included. Fifty studies with term controls were combined with the 36 studies from our previous systematic review, including 7094 preterm-born and 17 700 term-born participants. Of these studies, 45 included preterm-born children without BPD, 29 reported on BPD28 (supplemental oxygen dependency at 28 days), 26 reported on BPD36 (supplemental oxygen dependency at 36 weeks' postmenstrual age), and 86 included preterm-born participants. Compared with the term-born group, the group of all preterm-born participants (all preterm) had deficits of %FEV1 of -9.2%; those without BPD had deficits of -5.8%, and those with BPD had deficits of approximately -16% regardless of whether they had BPD28 or BPD36. As year of birth increased, there was a statistically significant narrowing of the difference in mean %FEV1 between the preterm- and term-born groups for the all preterm group and the 3 BPD groups but not for the preterm-born group without BPD. For the all BPD group, when compared with Scandinavia, North America and western Europe had deficits of -5.5% (95% CI, -10.7 to -0.3; P = .04) and -4.1% (95% CI, -8.8 to 0.5; P = .08), respectively.
Conclusions and relevance:
Values for the measure %FEV1 were reduced in preterm-born survivors. There were improvements in %FEV1 over recent years, but geographical region had an association with later %FEV1 for the BPD groups.
Treatment of respiratory distress syndrome (RDS) with surfactant replacement therapy in prematurely born infants was introduced more than 30 years ago; however, the surfactant preparations currently in clinical use are extracts from animal lungs. A synthetic surfactant that matches the currently used nature-derived surfactant preparations and can be produced in a cost-efficient manner would enable worldwide treatment of neonatal RDS and could also be tested against lung diseases in adults. The major challenge in developing fully functional synthetic surfactant preparations is to recapitulate the properties of the hydrophobic lung surfactant proteins B (SP-B) and SP-C. Here, we have designed single polypeptides that combine properties of SP-B and SP-C and produced them recombinantly using a novel solubility tag based on spider silk production. These Combo peptides mixed with phospholipids are as efficient as nature-derived surfactant preparations against neonatal RDS in premature rabbit fetuses.
Background:
Limited supply and complicated manufacturing procedure of animal-derived surfactants make the development of synthetic surfactants warranted. The synthesis of surfactant protein (SP)-B and SP-C is complicated and several analogues have been developed. Mini-BLeu is an analogue that corresponds to the first and last helix of SP-B joined by a loop and linked by 2 disulphide bridges. SP-C33Leu is an SP-C analogue that can be cost-efficiently produced, but no such analogue has yet been described for SP-B.
Objective:
To design short SP-B analogues which lack disulphide bridges, are easy to produce and are efficacious in a preterm rabbit fetus model of neonatal RDS.
Methods:
Synthetic surfactants were prepared by adding 2 or 8% (w/w) of synthetic variants of Mini-B27, similar to Mini-BLeu but with a short loop, or different peptides covering helix 1 of SP-B to 2% (w/w) of SP-C33Leu in 80 mg/mL of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/egg yolk phosphatidylcholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, 50: 40: 10 (by weight). Premature newborn rabbit fetuses were treated with 200 mg/kg of the surfactant preparations and ventilated with defined pressures for 30 min without positive end-expiratory pressure. Tidal volumes were registered during the experiments and lung gas volumes were measured at the end of the ventilation period.
Results:
Synthetic surfactant containing the Mini-B27 analogue with 2 disulphides gives similar lung gas volumes as treatment with an animal-derived surfactant preparation, but all other SP-B analogues gave lower lung gas volumes. All synthetic surfactants studied gave no significant differences in compliances except the surfactant containing the Mini-B27 analogue without cysteines that performed somewhat better at 30 min.
Conclusion:
The helix-loop-helix SP-B analogues tested in this study require the presence of 2 disulphide bridges for optimal activity in a rabbit RDS model.
Treatment of neonatal respiratory distress syndrome (RDS) using animal derived lung surfactant preparations has reduced the mortality of handling premature infants with RDS to a 50th of that in the 1960‐ies. The supply of animal derived lung surfactants is limited and only a part of the preterm babies is treated. Thus, there is a need to develop well‐defined synthetic replicas based on key components of natural surfactant. A synthetic product that equals natural derived surfactants would enable cost‐efficient production and could also facilitate development of treatments of other lung diseases than neonatal RDS. Recently the first synthetic surfactant that contains analogues of the two hydrophobic surfactant proteins B (SP‐B) and SP‐C entered clinical trials for treatment of neonatal RDS. Development of functional synthetic analogues of SP‐B and SP‐C, however, is considerably more challenging than anticipated 30 years ago when the first structural information of the native proteins became available. For SP‐B a complex three‐dimensional dimeric structure stabilized by several disulphides has necessitated the design of miniaturized analogues. The main challenge for SP‐C has been the pronounced amyloid aggregation propensity of its transmembrane region. Development of a functional non‐aggregating SP‐C analogue that can be produced synthetically was achieved by designing the amyloidogenic native sequence so that it spontaneously forms a stable transmembrane α‐helix.
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The breathing pattern of preterm infants is immature and is associated with a variety of reflexes. In a patient on the ventilator these reflexes interfere with spontaneous breathing. A better understanding of the immature control of breathing could lead to further improvements in ventilatory techniques. This thesis concerns studies of pulmonary stretch receptor (PSR) and phrenic nerve activity as part of the regulation of breathing in an animal model.
During assist/control ventilation with three different inspiratory pressure waveforms in animals with healthy lungs, squarewave pressure waveform strongly inhibits spontaneous inspiratory activity.
During partial liquid ventilation (PLV) in animals with healthy lungs, all PSRs studied maintained their phasic character, with increased impulse frequency during inspiration. PSR activity was not higher during PLV than during gas ventilation (GV), indicating that there was no extensive stretching of the lung during PLV.
During proportional assist ventilation (PAV) the applied airway pressure is servo-controlled proportionally to the ongoing breathing effort, thereby interacting with the activity of PSRs. Peak PSR activity was higher and occurred earlier during PAV than during CPAP. The regulation of breathing is maintained during PAV in surfactant-depleted animals before and early after surfactant instillation, with a higher ventilatory response and a lower breathing effort than during CPAP in both conditions.
Both lung mechanics and gas exchange influence the regulation of breathing. Inhibition of inspiratory activity occurred at a lower arterial pH and a higher PaCO2 during PLV than during GV in animals with surfactant-depleted lungs, which might be related to recruitment of a larger number of pulmonary stretch receptors during PLV.
In summary, selected aspects of the regulation of breathing were studied in an animal model with different ventilatory techniques under different lung conditions similar to those that can occur in infants.
Surfactant replacement therapy has been clearly shown to reduce requirements for mechanical ventilation, decrease the incidence of air leak complications, and improve survival in premature infants. Issues surrounding the efficacy of natural versus synthetic surfactant preparations, the timing, method, and frequency of the administration, and potential complications are reviewed.
Chronic respiratory disorders in the early days of the life of a newborn, i.e., during the first 4 weeks after birth, often become apparent as the result of aggressive treatment of acute respiratory disorder, such as bronchopulmonary dysplasia. Other respiratory disorders, often not related to pulmonary disorders, develop slowly, symptomless, and remain unnoticed for a long period of time, like hemangioma of the larynx or of the trachea. Acute respiratory disorders also very often are so symptomatic just after birth that they have to be treated immediately within the first hours of life.
Neonatal respiratory distress syndrome remains a major cause of death and disability in babies. Death is often associated with development of acute complications such as pneumothorax and intraventricular haemorrhage (IVH). Long term disability may result from the sequelae of IVH or bronchopulmonary dysplasia.
Surfactant replacement therapy for the treatment of respiratory distress syndrome (RDS) and other respiratory diseases in newborns has become one of the most active research areas in neonatology. This research has resulted in improved survival for preterm babies since becoming a routine treatment in the 1990s. The main characteristics of pulmonary surfactant, including its composition, pool, metabolism, inactivation and immediate effects after administration, are well-established. However, some doubts still remain about the use of exogenous surfactants and must be addressed. The new generation of synthetic surfactants has raised questions regarding the choice of surfactant type, the ideal timing for treatment (prophylactic vs early rescue strategy), the adequate dose and number of doses, new administration routes and the effects of the association between the use of antenatal steroids and the surfactant replacement therapy. There is also controversy surrounding the choice between early surfactant administration and the use of a nasal CPAP as an initial strategy to treat RDS and to reduce bronchopulmonary dysplasia (BPD). This article reviews basic and clinical aspects of surfactant replacement therapy for RDS and other respiratory diseases in newborns.
The long-term outcome of infants with severe respiratory distress syndrome can be improved by optimizing surfactant therapy and minimizing the risk for pulmonary barovolutrauma and oxygen toxicity. The authors hypothesized that this may be achieved with low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R), in combination with intratracheal instillation of a large fluid volume with diluted surfactant. Lung lavaged rabbits were initially ventilated with continuous positive pressure ventilation. The rabbits were randomized to treatment with LFV-ECCO2R and surfactant (experimental group), or surfactant only (control group). In the experimental group, the rabbits were treated with a large volume (16 ml/kg) of diluted surfactant (6.25 mg/ml) at a dose of 100 mg/kg body weight. After surfactant therapy, the FiO(2) 100% was gradually decreased. During 4 hours, the extracorporeal bloodflow was adjusted to maintain the PaCO2 between 4.0-6.0 kPa. Thereafter, the rabbits were allowed to breathe spontaneously with 2.5 cm H2O continuous positive airway pressure ventilation (CPAP) and 40% oxygen. In the control group, the rabbits received the same surfactant therapy. During the study period, the rabbits remained ventilated with an inspiratory oxygen concentration (FiO(2)) of 100% for 4 hours. The ventilator flow was adjusted to maintain the PaCO2 between 4.0 and 6.0 kPa. Thereafter, positive-end expiratory pressure was decreased to 2.5 cm H2O and FiO(2) was gradually decreased to 40%. In the experimental group, FiO(2) was decreased to 40% in a stepwise fashion whereby the PaO2 could be maintained easily within the normal range. Extracorporeal flow rates during perfusion ranged from 20-35 ml/kg/min and were sufficient to keep the PaCO2 and pH within normal limits. After 4 hours, the rabbits could breathe spontaneously with CPAP and 40% oxygen, while normal blood gas values were maintained. All rabbits survived the experiment. In the control group, all rabbits experienced severe hypoxemia, despite FiO(2) of 100% oxygen and, during the course of weaning, all rabbits died because of hypoxia. In conclusion, the present study demonstrated that barovolutrauma due to mechanical ventilation, and oxygen toxicity due to high FiO(2), can be minimized in an animal model of acute respiratory failure by the combination of LFV-ECCO2R and surfactant therapy.
Surfactant deficiency was identified as the cause of respiratory distress syndrome (RDS) as long ago as 1959. Trials of surfactant replacement in the 1960s were unsuccessful because the preparations used contained only phospholipids and they were administered inefficiently by nebulization. In the 1970s Bengt Robertson and Göran Enhörning showed that natural surfactant, containing both phospholipids and proteins, could ameliorate the signs of RDS in immature rabbits. In the 1980s Bengt Robertson and Tore Curstedt developed a porcine surfactant, Curosurf® (named after their surnames), which was effective in immature animals and was used in a pilot clinical trial beginning in 1983. Subsequent randomized clinical trials were planned a year later by Bengt Robertson, Tore Curstedt and Henry Halliday, and the first trial was begun in 1985. This showed that Curosurf reduced pulmonary air leaks and neonatal mortality in preterm infants with severe RDS. A second trial, coordinated by Christian Speer, demonstrated that multiple doses of Curosurf were more effective than a single dose. Subsequent trials conducted by the Collaborative European Multicenter Study Group, which included among others Guilio Bevilacqua, Janna Koppe, Ola Saugstad, Nils Svenningsen and Jean-Pierre Relier, showed that early treatment was more effective than later administration and that infants treated at birth had similar neurodevelopmental status to untreated controls at a corrected age of 2 years. Members of the Collaborative European Multicenter Study Group in Denmark and Sweden performed studies to demonstrate the benefits of a combination of surfactant treatment and early continuous positive airway pressure. Curosurf has also been compared with several synthetic and natural surfactants, and at a dose of 200 mg/kg Curosurf has been shown to be superior to either Survanta® or Curosurf used at a dose of 100 mg/kg. Recently, new-generation synthetic surfactants containing both phospholipids and proteins have been developed. After preclinical testing, CHF5633 (developed by Tore Curstedt and Jan Johansson in collaboration with Chiesi Farmaceutici) has undergone a preliminary first study in humans under the guidance of Christian Speer. If effective, this new surfactant preparation could revolutionize the treatment of preterm infants worldwide as it could be made consistently and safely in almost unlimited quantities. This story of a porcine surfactant preparation has been truly remarkable, and many thousands of preterm babies worldwide are now alive and well because of it. © 2015 S. Karger AG, Basel.
There is mounting evidence that early continuous positive airway pressure (CPAP) from birth is feasible and safe even in very preterm infants. However, many infants will develop respiratory distress syndrome (RDS) and require surfactant treatment. Combining a noninvasive ventilation approach with a strategy for surfactant administration is important to ensure optimal outcome, but questions remain about the optimal timing, mode of delivery and value of predictive tests for surfactant deficiency. Key findings in this review include the following: (1) a noninvasive ventilation strategy with CPAP from birth has a similar outcome to routine intubation in the delivery room; (2) prophylactic surfactant treatment has no advantage over early CPAP with selective surfactant administration; (3) surfactant during CPAP can be safely administered by rapid intubation-extubation (the INSURE method or via tracheal placement of a thin catheter), and (4) predictive tests for surfactant deficiency are being developed and might in future aid in directing surfactant treatment to infants at risk of developing severe RDS. A strategy for surfactant administration should be part of a noninvasive ventilation approach for preterm infants at risk of developing significant RDS. The different methods for surfactant administration during CPAP are reviewed here. © 2015 S. Karger AG, Basel.
Background: Exogenous surfactant is a mainstay of neonatal care, however, time-dependent changes in respiratory function during the peri-surfactant period are not well known. This critical time contributes to baro- and volu-trauma effects, heralding chronic lung disease. The purpose of the study was to determine real-time changes in respiratory function minute-by-minute during the immediate post-surfactant period and determine the effect of increased PEEP on these parameters. Methods: Thirty, time-pregnant, Sprague-Dawley rat pups received surfactant or phosphate buffered saline (PBS) control between post-natal age 10 and 12 days. Airway resistance, compliance, tissue dampening, elastance, eta (ratio of dampening to elastance), were measured at PEEPs of 3 and 6 cm H 2O at 1, 2, 5, 8, 12 and 15-minutes. Pressure-Volume curves were generated. Student's t-test of running averages of each respiratory function parameter were used for comparison. Results: At PEEP of 6 cm H 2O, airway resistance remained elevated at 12 minutes (p < 0.01), but was significantly lower by 8 minutes in the group at PEEP of 3 cm H 2O (p < 0.05). Increased PEEP led to an earlier changes in tissue dampening (2 min vs. 8 min, p < 0.01), earlier increases in elastance (5 min vs. 8 min, p < 0.05), and an earlier alteration in eta (2 min vs. 15 min, p < 0.01). Time dependent pressure-volume loops demonstrated significant decreases in variability within 2 minutes at PEEP of 3 (p < 0.001). The PV curves were normalized at 5 minutes. Conclusions: Acute minute-by-minute changes occur in airway resistance, elastance, compliance, eta and tissue damping occur following surfactant delivery, but normalize by 15 minutes. At higher PEEPs, respiratory parameters normalized earlier and variability in PV curves was reduced. Consideration of the time-dependent nature of respiratory function changes in the peri-surfactant period may improve administration.
At 33 hospitals in the United States, a double-blind, randomized clinical trial was performed to compare one versus three prophylactic doses of synthetic surfactant in 700 to 1100 gm inborn infants. All 826 infants received an initial prophylactic dose of surfactant within 30 minutes of birth. Subsequently 410 infants received two doses of placebo (air) 12 and 24 hours later, and 416 infants received two additional doses of surfactant. By the age of 28 days, 70 infants who received one dose of surfactant and 40 infants who received three doses were dead, a 43% relative reduction in the mortality rate (30 fewer deaths; p = 0.002). By the age of 1 year after term, 87 infants who received one dose and 62 infants who received three doses were dead: a 29% relative reduction in the mortality rate (25 fewer deaths; p = 0.027). Infants who received three doses of surfactant required significantly less oxygen and less mean airway pressure for the first week of life. Necrotizing enterocolitis (9 vs 25 infants; p = 0.005), and use of high-frequency ventilation (13 vs 26 infants; p = 0.037); pancuronium (43 vs 62 infants; p = 0.045); and leukocyte transfusions (0 vs 4 infants; p = 0.042) were less frequent in the three-dose group, but air leak, bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and infections were not different. These results indicate that physiologic findings, mortality rates, and probably morbidity rates are improved by two additional prophylactic doses of synthetic surfactant. (J PEDIATR 1995;126:969-78)
A three-dose prophylactic regimen of synthetic surfactant replacement has been shown to improve neonatal and 1-year survival rates in infants of 700 to 1100 gm birth weight when compared with a single prophylactic dose. The purpose of this study was to evaluate the growth, development, and late morbidity at 1 year adjusted age among the survivors of the 826 patients enrolled in the protocol. Complete follow-up data were obtained for 75% of the survivors in both groups. Chronic lung disease, need for respiratory support, neurologic disease requiring medication, visual or auditory impairments, and the incidence and severity of retinopathy of prematurity were equivalent in the two groups. The frequency of neurodevelopmental impairment was also comparable in the groups that received one dose versus three doses: moderate to severe cerebral palsy was found in 9% versus 6%, mental retardation assessed by Bayley Scales of Infant Development scores less than 69 was found in 16% vs 14%, and moderate to severe impairments of any kind were found in 33% vs 24%, respectively. Furthermore, the absolute number of impaired survivors was 92 in the three-dose group versus 106 in the one-dose group, despite a higher survival rate in the three-dose group. This study demonstrates that developmental outcomes of infants weighing 700 to 1100 gm who received three prophylactic doses of synthetic surfactant are at least as good as those of infants receiving a single dose, and that improving survival rates of very premature infants with synthetic surfactant does not result in increased numbers of infants with impairments. (J P EDIATR 1995;126:S26-32)
The effect of a 50% increment or decrement in the recommended 5 ml/kg dose of a commercially available surfactant (Exosurf Neonatal) on the alveolar-arterial oxygen gradient was investigated in a multicenter, double-blind, placebo-controlled rescue trial conducted at 15 hospitals in the United States. Two doses of three different volumes (2.5, 5.0, and 7.5 ml/kg) were compared with two 5.0 ml/kg doses of air in 281 infants weighing ≥ 1250 gm who had respiratory distress syndrome requiring mechanical ventilation and an arterial/alveolar oxygen ratio < 0.22. The first dose was given between 2 and 24 hours of age, and the second dose was given 12 hours later to all infants who still required mechanical ventilation. Infants were stratified at entry by gender and the magnitude of the arterial/alveolar oxygen ratio. The air placebo arm of the study was terminated early when reductions in mortality rates were proved in another rescue trial of this surfactant in infants with the same birth weights. For the first 48 hours, administration of a 2.5 ml/kg dose of surfactant provided less improvement in the alveolar-arterial oxygen gradient than doses of 5.0 and 7.5 ml/kg, which were equivalent. Similar results were observed in mean airway pressure (p < 0.05). There were no significant differences among the three dosage groups in mortality rate, air leak, bronchopulmonary dysplasia, and other complications of prematurity. There were no pulmonary hemorrhages in any group. Reflux of surfactant occurred more frequently in the 5.0 and 7.5 ml/kg groups. These results indicate that more sustained improvements in oxygenation are provided, with equal safety, by the standard two 5.0 ml/kg rescue doses of this surfactant than by the 2.5 ml/kg dose. No further benefit is gained from two larger doses given 12 hours apart. (J PEDIATR 1994;124:294-301)
In a multicenter, double-blind, placebo-controlled trial conducted at 23 hospitals in the United States, a single prophylactic 5 ml/kg dose of a synthetic surfactant (Exosurf Neonatal) or air placebo was administered shortly after birth to 215 infants with birth weights of 500 to 699 gm. Despite stratification at entry by birth weight and gender, by chance female infants predominated in the air placebo group and male infants predominated in the surfactant group. Among infants receiving synthetic surfactant, improvements in oxygen requirements were significant at 2 hours after birth (p = 0.014) and persisted for 3 days (p = 0.001); improvements in the alveolar-arterial partial pressure of oxygen gradient were significant at 6 hours after birth (p = 0.01) and persisted for 3 days (p = 0.008). Improvements in mean airway pressure were not significant at 2 or at 6 hours after birth (p = 0.622 and 0.083, respectively), but became significant thereafter and persisted for 3 days (p = 0.002). Pneumothorax was reduced by slightly more than half (25 vs 11; p = 0.014); death from respiratory distress syndrome (RDS) was also reduced (26 vs 15; p = 0.046). Overall neonatal mortality, however, was not significantly reduced (58 vs 46; p = 0.102). Other complications of RDS and prematurity were not altered, except that pulmonary hemorrhage occurred significantly more frequently in infants receiving synthetic surfactant (2 vs 12; p = 0.006). These findings indicate that a single prophylactic dose of synthetic surfactant in infants weighing 500 to 699 gm at birth improves lung function, incidence of air leak, and death from RDS but not overall mortality. The only safety problem identified was an increase in pulmonary hemorrhage.
In a multicenter, double-blind, placebo-controlled rescue trial conducted at 21 American hospitals, two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air were administered to 419 infants weighing 700 to 1350 gm who had respiratory distress syndrome and an arterial/alveolar oxygen pressure ratio <0.22. The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later to those infants remaining on ventilatory support. Infants were stratified at entry by birth weight and gender. Among infants receiving synthetic surfactant, improvements in alveolar-arterial oxygen pressure gradient, arterial/alveolar oxygen pressure ratio, and oxygen and ventilator needs through 7 days of age were apparent. Death from respiratory distress syndrome was reduced by two thirds (21 vs 7; p=0.007), and the overall neonatal mortality rate was reduced by half (50 vs 23; p=0.001). Although there was no significant reduction in the incidence of bronchopulmonary dysplasia (39 vs 31; p=0.107), the hypothesis that survival through 28 days without bronchopulmonary dysplasia would be enhanced by two rescue doses of synthetic surfactant was proved true (21% improvement, from 132 to 156 patients; p=0.001). In addition, the incidence of pneumothorax was reduced by one third (62 vs 40; p=0.022), and the incidence of pulmonary interstitial emphysema was reduced by half (102 vs 51; p=0.001). The only side effect identified was an increase in the incidence of apnea (102 vs 134; p=0.001). These findings indicate that rescue use of a synthetic surfactant can improve the morbidity and mortality rates for premature infants with respiratory distress syndrome.
AIM To develop and evaluate a score which quantifies mortality risk in very low birthweight (VLBW) infants (birthweight below 1500 g) at admission to the neonatal intensive care unit. METHODS Five hundred and seventy two VLBW infants admitted from 1978 to 1987 were randomly assigned to a cohort (n = 396) for score development and a cohort (n = 176) for score validation. Two hundred and ninety four VLBW infants admitted from 1988 to 1991 were used to compare risk adjusted mortality between the two eras. RESULTS Using multiple regression analysis, birthweight, Apgar score at 5 minutes, base excess at admission, severity of respiratory distress syndrome, and artificial ventilation were predictive of death in the development cohort. According to regression coefficients, a score ranging from 3 to 40 was developed. At a cutoff of 21, it predicted death in the validation cohort with a sensitivity of 0.85, a specificity of 0.73, and a correct classification rate of 0.76. The area under the receiver operating characteristic curve was 0.86. There was no significant difference in risk severity and in risk adjusted mortality between the eras 1978–87 and 1988–91. CONCLUSION The present score is robust, easily obtainable at admission, and permits early randomisation based on mortality risk.
Objetivo: El propósito de nuestro estudio fue conocer el déficit neurosensorial a los 2 años de edad corregida (EC) en niños con antecedentes de muy bajo peso de nacimiento (MBPN) en control en el policlínico de seguimiento del Servicio de Recién Nacidos del Hospital Dr. Sótero del Río, Santiago, Chile. Método y participantes: 254 RN de 268 sobrevivientes de un total de 424 RNMBPN nacidos entre 1994 a 1996 fueron seguidos prospectivamente por un equipo multidisciplinario, que realiza evaluación clínica, neurológica, auditiva y psicomotora. Del grupo en seguimiento: 181 niños, que representa el 71% del grupo, completan adecuadamente los controles. Resultados: Treinta y dos por ciento (59/181) de los niños tiene una evaluación neurosensorial anormal a los 24 meses de EC; 13% (24/181) presenta anormalidad neurosensorial severa: 6,6% (12/181) parálisis cerebral, 6% coeficiente del desarrollo mental menor de 70,3% sordera neurosensorial severa bilateral y 1 presentó ceguera. La mitad de los niños con parálisis cerebral presentan además otra secuela severa. Los factores asociados significativamente con evolución neurosensorial anormal fueron peso de nacimiento menor de 1 000 g, hemorragia intraventricular grados 3 y 4, convulsiones, apneas y ductus. En análisis de regresión logística, la apnea fue significativa e independientemente asociada a evolución neurosensorial anormal. (Palabras clave: RNMBPN, pretérmino, seguimiento, neurosensorial, parálisis cerebral, factores prenatales y postnatales).
Both prophylactic and early surfactant (SF) replacement therapy reduce pulmonary complications and mortality in ventilated infants with respiratory distress syndrome (RDS). The effectiveness of one or more doses and the impact on morbidity and mortality of premature neonates with RDS need to be further clarified. The objective of this study was to investigate the necessity of repeated surfactant replacement therapy in premature infants ≤32 weeks of gestational age and the possibility of an underlying pathology. This study included 126 premature neonates of 24-32 weeks of gestation. We used 200 mg/kg per dose of porcine surfactant (Curosurf®) as primary treatment and 100 mg/kg in cases that required retreatment. The subjects were classified into two groups: the first group (Group 1) received a single dose of surfactant (n=98) and the second group (Group 2) included infants who required more than one dose (n=28). The 1st dose was administered in the first 20 minutes after birth while the second was given six hours later. In four cases, a 3rd dose was required, that was provided 12 hours after birth. Recorded data included: clinical and radiological classification of RDS, extubation time, oxygenation estimation indexes (OI: oxygenation index, A-aDO2: alveolar-arterial oxygen difference, a/APO2: arterial-alveolar ratio of partial oxygen pressure), requirement and duration of oxygen administration, total duration of mechanical ventilation, and survival rate. Patient Group 1 did not present any radiological findings of RDS of grade 3 or 4 six hours after SF administration, whereas such findings were recorded in three neonates of Group 2. Therefore, we assumed that failure of a single-dosing treatment indicates a more severe RDS and might reflect an underlying pathology. The impact of maternal chorioamnionitis in the neonates that necessitated further replacement therapy was statistically significant (p=0.045); moreover, infection markers were positive in the majority of the patient population of the second group. Twenty-two neonates (22%) of the first group needed intubation in the delivery room compared to 16 (57%) of the second group (p=0.0001). In conclusion, premature infants treated with a single dose of surfactant can usually be successfully extubated. Requirement of retreatment could be attributed to other pathogenetic mechanisms. A positive history of maternal chorioamnionitis was the commonest reason.
Respiratory distress syndrome (RDS) is the leading cause of neonatal morbidity and mortality in premature infants. It is caused by surfactant deficiency and lung immaturity. Lucinactant is a synthetic surfactant containing sinapultide, a bioengineered peptide mimic of surfactant-associated protein B. A meta-analysis of clinical trials demonstrates that lucinactant is as effective as animal-derived surfactants in preventing RDS in premature neonates, and in vitro studies suggest it is more resistant to oxidative and protein-induced inactivation. Its synthetic origin confers lower infection and inflammation risks as well other potential benefits, which may make lucinactant an advantageous alternative to its animal-derived counterparts, which are presently the standard treatment for RDS.
Two clinical pilot studies were accomplished. The first focused on the administration of alpha-1 proteinase inhibitor to patients with the adult respiratory distress syndrome and had the goals of determining safety, describing pharmacokinetic parameters, and determining whether intravenous administration would augment functional antiprotease activity of blood and/or bronchoalveolar lavage fluid. Results indicate; (1) administration of alpha-1 PI was safety; (2) both initial and steady state clearance of alpha-1 from the central volume of distribution were enhanced; (3) infused alpha-1 retained all of its functional activity; (4) lung lavage levels of alpha-1 did not increase after intravenous infusion of alpha-1 PI; and (5) the calculated of the infused alpha-1 PI to those levels was significant. The second pilot study focused on the possible benefits to gas exchange and lung compliance that might accompany administration of exogenous lung surfactant to patients within the first 48 hours of development of ARDS.
Respiratory distress syndrome (RDS) is primarily due to decreased production of pulmonary surfactant, and it is associated with significant neonatal morbidity and mortality. Exogenous pulmonary surfactant therapy is currently the treatment of choice for RDS, as it demonstrates the best clinical and economic outcomes. Studies confirm the benefits of surfactant therapy to include reductions in mortality, pneumothorax, and pulmonary interstitial emphysema, as well as improvements in oxygenation and an increased rate of survival without bronchopulmonary dysplasia. Phospholipids (PL) and surfactant-associated proteins (SP) play key roles in the physiological activity of surfactant. Different types of natural and synthetic surfactant preparations are currently available. To date, natural surfactants demonstrate superior outcomes compared to the synthetic surfactants, at least during the acute phase of RDS. This disparity is often attributed to biochemical differences including the presence of surfactant-associated proteins in natural products that are not found in the currently available synthetic surfactants. Comparative trials of the natural surfactants strive to establish the precise differences in clinical outcomes among the different preparations. As new surfactants become available, it is important to evaluate them relative to the known benefits of the previously existing surfactants. In order to elucidate the role of surfactant therapy in the management of RDS, it is important to review surfactant biochemistry, pharmacology, and outcomes from randomized clinical trials.
Severe respiratory failure is always associated with a defect in the surfactant system. Surfactant substitution in newborn infants with respiratory distress syndrome (RDS) has gained worldwide acceptance. In the present study, we have evaluated whether surfactant diagnostics are of use in choosing recipients of exogenous surfactant. In addition, we studied whether factors apparently unrelated to surfactant influence the degree of respiratory failure and surfactant responsiveness. In small preterm infants, the surfactant indices in amniotic fluid (L/S ratio and phosphatidylglycerol), within 3 days of birth, predicted the risk of RDS with a sensitivity of 90–100%, and a specificity of 50–85%. The surfactant indices, measured in BAL, predicted the risk of ARDS (which became evident 1 to 7 days later) with a sensitivity of 50–60% and a specificity of 59–65%. In small preterm infants with RDS, the amount of fluids given during the first day correlated positively with the degree of respiratory failure and negatively with the degree of surfactant responsiveness. According to an experimental study, in hydrostatic lung edema, exogenous surfactant is diluted by edema fluid and becomes sensitive to inhibitors of surfactant function. Beside dosage, quality, and time of administration, the management of patients largely dictates the responsiveness to exogenous surfactant.
As part of a multicenter surfactant rescue study, the chest X-rays of 239 preterm and term infants were analyzed. To study the influence of surfactant administration on radiographic appearance, 130 patients with a clinical and radiological diagnosis of typical respiratory distress syndrome were selected, in whom adequate chest x-rays before and within 48 h after treatment were available. Median gestational age was 30 weeks (range 25–38 weeks), median birth weight was 1335 g (range 625–3450). The time of surfactant application ranged between 90 min and 24 h after birth (median 6 h). The most common finding after surfactant administration was uniform (n=47) or disproportionate (n=46) improvement of pulmonary aeration, which showed a significant correlation to posttreatment reduction of oxygen requirement (pn=24, including three patients with pneumothorax) after surfactant treatment was an unfavourable prognostic sign. 54% of these patients (13 of 24) died within the first month of life, compared to 8% (7 of 93) in the group of patients with initial improvement of ventilation.
To evaluate the effects of surfactant administration on the neonatal brain using 3-channel neonatal electroencephalography (EEG).
A prospective cohort of 30 infants had scalp electrodes placed to record brain waves using 3-channel EEG (Fp1-O1, C3-C4, and Fp2-O2). Sixty-second EEG epochs were collected from a 10-minute medication-free baseline, during premedication for endotracheal intubation, at surfactant administration, and at 10, 20, and 30 minutes after surfactant administration for amplitude comparisons. Oxygen saturation and heart rate were monitored continuously. Blood pressure and transcutaneous carbon dioxide were recorded every 5 minutes.
Eighteen of 29 infants (62%) exhibited brain wave suppression on EEG after surfactant administration (P ≤ .008). Four of those 18 infants did not receive premedication. Nine infants exhibited evidence of EEG suppression during endotracheal intubation, all of whom received premedication before intubation. Five infants had EEG suppression during endotracheal suctioning. Oxygen saturation, heart rate, and blood pressure were not independent predictors of brain wave suppression.
Eighteen of 29 intubated infants (62%) had evidence of brain wave suppression on raw EEG after surfactant administration. Nine patients had evidence of brief EEG suppression with endotracheal intubation alone, a finding not previously reported in neonates. Intubation and surfactant administration have the potential to alter cerebral function in neonates.
Nasal continuous positive airway pressure (nCPAP) is an effective treatment of respiratory distress syndrome. Due to long-standing experience of early nCPAP as the primary respiratory support option in preterm infants, this approach is sometimes labeled 'the Scandinavian Model'. Mechanical ventilation is potentially harmful to the immature lungs and cohort studies have demonstrated that centers using more CPAP and less mechanical ventilation have reduced rates of bronchopulmonary dysplasia. However, there is a lack of evidence in the form of larger, randomized controlled trials to prove the superiority of either method. Surfactant is essential in the treatment of respiratory distress syndrome and has generally been reserved for infants on mechanical ventilation. With the development of INSURE (INtubation SURfactant Extubation), in which surfactant is administered during a brief intubation followed by immediate extubation, surfactant therapy can be given during nCPAP treatment further reducing need for mechanical ventilation. In this review the history, current knowledge and techniques of CPAP and surfactant are discussed.
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