Normally, the first clinical manifestation of BPD begins 8–14 days after birth, and in the first days and weeks of life vulnerable preterm lungs are exposed to several hits. Thus, the mode of ventilation in the delivery room (18), MV (15–17), oxygen treatment, prenatal (64) and neonatal infections (16,65) may all (66) influence the development and severity of the BPD. Nutrition and heritability also play a role.
nCPAP vs. MV and BPD
Conventionally, MV may damage the lungs (15), and the incidence of BPD was low in centres with a long tradition of primary treatment of RDS via nCPAP compared with MV (22,23,39,67). In a multivariate analysis comparing the outcome in VLBW weight infants from centres using primary nCPAP and MV, BPD was explained simply by the incidence of MV (50). In the COIN study (24) with contributions from centres with a relatively recent tradition of using nCPAP, a trend towards less BPD was found in the nCPAP group compared with the MV group. Many observational studies with the use of primary nCPAP vs. MV support the findings of diminished development of BPD when primary nCPAP was used (14,23,39,67). All these studies support the findings of a tight link between the use of MV and the development of BPD.
INSURE, surfactant treatment and BPD
Although the introduction of surfactant treatment has not reduced the incidence of BPD (68,69), there are strong indications and evidence that surfactant therapy has a positive effect on the development of BPD and on the severity of BPD in the individual patients. The incidence of BPD is less following treatment with prophylactic surfactant than after rescue treatment (70), and early selective surfactant treatment reduces the combined mortality and BPD more effectively than rescue treatment of infants mechanically ventilated (71). To this evidence are added the positive experiences obtained by INSURE. Thus, the incidence of BPD was very low in centres which introduced INSURE compared with centres using MV and rescue surfactant (8,9). At the time when INSURE was introduced in the early 1990s, the incidence of BPD on day 28 in premature infants with moderate-to-severe RDS was 9% vs. 30% in infants treated with MV and surfactant (Table 1). A Cochrane meta-analysis from 2009 including six studies indicates that early nCPAP with early surfactant compared with nCPAP with late surfactant significantly reduces BPD, the need for MV and air leaks (63). Most observational studies have also shown that INSURE may diminish the development of BPD. In a recent randomized trial comparing INSURE with nCPAP, the incidence of MV, air leaks and BPD was less in the INSURE group (74). Another U.S. group reduced the incidence of chronic lung disease in infants < 1500 g by avoiding intubation in the delivery room, the adoption of new pulse oximeter limits and the early use of nCPAP and surfactant (75).Very recently, the reported results from the CURPAP study (76) showed no differences in the need for MV after prophylactic vs. early rescue surfactant in extremely preterm infants on nCPAP. The incidence of BPD and pneumothorax was very low in both treatment groups. As mentioned, the positive clinical results with INSURE are supported by animal experiences (15,31).
Table 1. Gestational age, birth weight and outcome from three randomized clinical trials in the early 1990s including infants with severe RDS with entry criteria: a/APO2 < 0.22
|Characteristics and outcome||Primary nCPAP + Curosurf (INSURE)† n = 68 ||MV + Exosurf‡ n = 6757||MV + Curosurf§ n = 2168 |
|Gestational age (weeks)||29.5||29.6||29.4|
|Birth weight (g)||1352||1413||1374|
|Oxygen dependency at 28 days (%)||9*||29*||30*|
|Intracerebral haemorrhage grades 3 or 4 (%)||12||15||14|
|Retinopathy stages 3 or 4 (%)||3||1||2|
|Necrotising enterocolitis (%)||0||3||6|
|Patent ductus arteriosus (%)||28||22||35|
Probably the main effect of surfactant is, indirectly, improving the ability of the infant to breathe supported by nCPAP and reducing the need for MV, thereby lessening barotraumas. The efficacy of this effect is dependent on the type of CPAP system, on the surfactant preparation and on the timing and dosing of the surfactant treatment.
A large database analysis of more than 24 000 preterm infants has demonstrated a lower mortality rate and reduced length of hospital stay with Curosurf compared with Survanta and Infasurf, associated with significant cost benefits (77). Infants treated with Curosurf show faster weaning of oxygen and less need for additional surfactant doses and 200 mg/kg is more effective than 100 mg/kg (78). The new synthetic surfactants are not yet licensed for RDS treatment. Comparative trials of lucinactant (KL4) with natural surfactants suggest equivalence, but further studies are needed to clearly demonstrate superiority.
Surfactant is administered intratracheally via an endotracheal tube or laryngeal mask. Bolus or rapid instillation gives optimal distribution; bagging is probably not necessary. Despite encouraging results with aerosolized surfactant in ventilated animal, nebulization of surfactant in the clinical setting has not yet been successful, although remains an attractive route of administration for further investigation.
Analgesia and sedation for elective intubation are recommended. Morphine is commonly used as premedication, but has limitations, such as delayed onset and a risk for apnoea in association with early extubation. In the INSURE protocol, the opioid effect is reversed with naloxone. Newer, short-acting drugs such as remifentanil are currently being evaluated in newborns with promising results (79).
Early INSURE combined with caffeine prophylaxis seems to be ideal for the prevention of BPD. Thus, treatment with caffeine citrate in a meta-analysis has been shown to reduce the development of BPD significantly (80), probably because this treatment reduces the need for MV. Although doxapram may be effective in caffeine resistant apnoea, the treatment is associated with various side-effects (81) and should at present be used only briefly or not at all in preterm infants.
Besides the known additive effect of prenatal steroids and INSURE on development of RDS (9), steroids also influence the development of BPD. Thus, it is likely that prenatal steroid treatment will have some negative effect on the development of BPD (64) in addition to the positive effect on RDS. Both early- and late-postnatal steroids reduce the incidence of BPD, but early-postnatal steroids may have serious side-effects such as cerebral palsy (82). Late-postnatal steroids seem to be safer, but there is no absolute safe window (83). NIPPV may be considered as prophylaxis or treatment to avoid severe apnoea and to diminish the development of BPD as mentioned above (58).
INSURE and modified INSURE for infants < 26–27 weeks gestation
To minimize unnecessary intubations, The European guidelines for treatment of RDS recommend prophylactic surfactant treatment for infants below 27 weeks of gestation (84). Because of that many clinicians prefer to treat these infants with prophylactic MV and surfactant from birth. As described this imply an increased risk of developing BPD compared with infants allowed to breathe via nCPAP from birth.
In the light of the results from the CURPAP study including infants of 25–28 weeks gestation (76), it can be recommended to treat infants in these age groups with nCPAP from birth and to use rescue INSURE. Another possibility is to install surfactant via a feeding catheter, prophylactically or very early. This procedure often gives infants less than 26 weeks of gestation the ability to breathe supported by nCPAP for long periods (85), and they also have low mortality and BPD compared to historical controls in the same neonatal units (85).