Nasal CPAP and surfactant for treatment of respiratory distress syndrome and prevention of bronchopulmonary dysplasia

Neonatal respiratory distress syndrome (nRDS) is the most important cause of mortality and morbidity in preterm infants. During the last 50 years, significant and conclusive progresses have been made in the understanding of the etiology and pathophysiology of this disease as well as in the development of new treatment strategies. However, the optimal treatment regimen is still under discussion. The introduction of nasal continuous positive airway pressure (nCPAP) has provided a great improvement in nRDS management, reducing by more than 50% the mortality rate in infants affected by this disease; the therapeutic options have been further enhanced by the development of mechanical ventilation (MV) techniques. Moreover, the introduction of prenatal steroids has significantly improved the clinical outcomes of premature infants at high risk of nRDS. Surfactant replacement therapy has been successfully used in clinical practice since 1980, with remarkable results. Furthermore, surfactant administration can be combined with nCPAP in order to maximize clinical benefits and prevent the incidence of bronchopulmonary dysplasia (BPD). The Scandinavian INtubation SURfactant Extubation procedure (INSURE) is a combination of nCPAP and surfactant, which has been proven to significantly reduce mortality when compared to nCPAP alone. This approach was first reported by Victorin in 1990 in spontaneously breathing infants, then further developed by Verder et al. in 1992. In brief, the INSURE approach is based on primary management of the infants with nCPAP in combination with early rescue surfactant administered through a transient period of intubation followed by rapid extubation to nCPAP. In 1994, the first randomized controlled trial of surfactant instillation during nCPAP showed that a single dose of surfactant reduced the need for MV from 85% to 43%. This effect was even more pronounced if surfactant was given as early rescue treatment, as demonstrated by another randomized study on very low birth weight (VLBW) infants. These findings were further supported by other studies, overall confirming the marked efficacy of the INSURE approach. Although the introduction of surfactant treatment has not reduced the incidence of BPD, there is strong evidence that surfactant therapy diminishes the development of BPD and its severity. It has been reported that the incidence of BPD is lower following treatment with prophylactic surfactant than after rescue treatment. Moreover, early selective surfactant treatment reduces the combined incidence of mortality and BPD more effectively than rescue treatment of infants undergoing MV. The experience with the INSURE approach further supports these results. In fact, the incidence of BPD was very low in centres which introduced INSURE into clinical protocols, when compared with centres using MV and rescue surfactant: some clinical trials conducted in the early 1990s showed that the incidence of BPD on day 28 in premature infants with moderate-to-severe RDS was 9% with the INSURE approach versus 30% reported in infants treated with MV and surfactant. Most observational and experimental studies conducted up to now have confirmed that INSURE may diminish the development of BPD. Furthermore, a very recent meta-analysis by the Cochrane Collaboration, including six studies, indicates that early nCPAP with early surfactant administration compared with nCPAP with late surfactant significantly reduces BPD, the need for MV and air leaks. The mechanisms of this effect are still under investigation. Surfactant is likely improving the ability of the infant to breathe supported by nCPAP only, thus reducing the need for MV and lessening barotrauma. However, the extent of this effect is dependent upon several factors, including the type of CPAP system, the surfactant preparation, and the timing and dosing of surfactant treatment. Different surfactant preparations may in fact be associated with different efficacy profiles. The analysis of a large database including more than 24,000 preterm infants has demonstrated a lower mortality rate and reduced length of hospital stay in those treated with Curosurf, compared with other preparations like Survanta and Infasurf; this more evident efficacy is also associated with significant cost benefits. Infants treated with Curosurf show faster weaning of oxygen and less need for additional surfactant doses. The comparison of different Curosurf regimens showed that the 200 mg/kg is more effective than 100 mg/kg, thus representing the most appropriate choice for different therapeutic strategies, including INSURE. The INSURE approach with Curosurf 200 mg/kg can be further improved with the prophylactic administration of caffeine citrate. A recent meta-analysis has demonstrated that treatment with caffeine significantly reduces the development of BPD. This effect may be due to the reduction of the need for MV determined by caffeine administration. Doxapram may represent a therapeutic alternative to caffeine citrate; however, although this drug may be effective in caffeine-resistant apnoea, it is associated with various side-effects and therefore should be used only for a short time, when necessary, in preterm infants. In conclusion, the combined use of non-invasive prophylaxis with prenatal steroids and early-postnatal treatment with INSURE has shown to decrease the severity and mortality of RDS and BPD. The optimal type of CPAP system and surfactant preparation, dosing and method of administration may significantly influence the outcome.

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