(4)
Department of Pediatrics, Neonatal Unit, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Educational Aims
To review the use of various pharmacologic agents in the prevention and treatment of neonatal respiratory disease
To specifically discuss the evidence for use of two most cost-effective interventions in neonatal medicine – antenatal steroids and surfactant replacement therapy
To discuss the role of inhaled nitric oxide and other cheaper alternatives like sildenafil, magnesium sulphate and adenosine in the management of pulmonary hypertension of the newborn
To review the status of various drugs for chronic lung disease
To dissect the role of the above strategies in low-resource settings
The survival rates of neonates suffering from respiratory failure have improved tremendously over the last three decades. This has occurred because of general improvements in the neonatal intensive care as well as widespread use of invasive and non-invasive respiratory support. Numerous technological advances have given us newer and far better ventilators as compared to a decade ago. However, the rates of chronic lung disease (CLD) have not decreased. It is realised that although CLD has a multifactorial pathogenesis, the single most important factor responsible for occurrence of CLD is probably the endotracheal tube. Hence, all efforts are made either to avoid intubation or to minimise the duration of intubation by taking help of many adjunctive therapies. However, many of these therapies, though used very commonly, are not based on strong evidence.
32.1.1 Antenatal Steroids
Though antenatal steroids are more of a preventive medicine, they need to be mentioned here because they are the most cost-effective intervention which can decrease the incidence and severity of respiratory distress syndrome (RDS) and hence its complications. In spite of this fact, use of antenatal steroids is not a routine practice in many developing countries and is suboptimally practised even in developed countries. The prenatal steroid use thus remains a case of missed opportunity. If fully scaled up, this intervention could save up to 500,000 neonatal lives annually (Mwansa-Kambafwile et al. 2010). Administration of antenatal corticosteroids to pregnant women at risk for premature delivery is associated with an overall reduction in neonatal death, RDS, intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), need for respiratory support, intensive care admissions and systemic infections in the first 48 h of life in a wide range of gestational ages from 26 to 346/7 weeks (Roberts and Dalziel 2006). Some guidelines recommend considering the use of antenatal steroids after 34 weeks’ gestation also if there is evidence of pulmonary immaturity (Committee on Obstetric Practice 2002; RCOG 1996; U.S. Department of Health and Human Services and Public Health 1994). The overall reduction in neonatal mortality with the use of antenatal steroids is to the tune of 60–69 % (Crowley et al. 1990; Doyle et al. 1986) and that of IVH by about 50 % (RCOG 1996). Others have reported reduction in the incidence of PDA (Papageogiou et al. 1989; National Institute of Health 1994). One study had shown a reduction in the incidence of CLD from 35 to 25 % with the use of antenatal steroids (Van Marter et al. 1990), but this has not been replicated by others. There is a potential benefit commencing within hours of the first dose. After one course (total of 24 mg of betamethasone or dexamethasone given over 48 h) of antenatal steroids, the maximum benefits are seen if the fetus is delivered 24 h after and within 7 days of the last dose (National Institute of Health 1994). However, use of antenatal steroids reduces neonatal deaths even when infants are born <24 h after the first dose (Roberts and Dalziel 2006). Another study has confirmed that incomplete courses of antenatal steroids are also beneficial (Elimian et al. 2003). It has also been shown that improved neonatal outcomes continue even beyond 7 days of the last dose (Goldenberg and Wright 2001). The choice is between betamethasone (12 mg intramuscularly every 24 h for 2 doses) and dexamethasone (6 mg intramuscularly every 12 h for 4 doses). Both betamethasone and dexamethasone are identical in biologic activity, readily cross the placenta, are devoid of mineralocorticoid activity, cause relatively weak immunosuppression and have longer duration of action (Ohrlander et al. 1975; Osathanoudh et al. 1977). However, recent trials have shown betamethasone is associated with a greater reduction in risk of death than dexamethasone, corroborating Jobe’s results in 2004 (Lee et al. 2006; Jobe and Soll 2004). Two other studies have indicated a decreased risk of cystic periventricular leukomalacia (PVL) in premature infants exposed to betamethasone, whereas this association was not found with dexamethasone (Baud et al. 1999; Spinillo et al. 2004).
Frank chorioamnionitis is usually considered a contraindication to the use of antenatal steroids. A recent review and meta-analysis, however, found encouraging results (Been et al. 2011). Seven observational studies were included in this review. In histological chorioamnionitis (5 studies), antenatal steroids were associated with reduced mortality (OR 0.45; 95 % CI 0.30–0.68; P = 0.0001), RDS (OR 0.53; 95 % CI 0.40–0.71; P < 0.0001), PDA (OR 0.56; 95 % CI 0.37–0.85; P = 0.007), IVH (OR 0.35; 95 % CI 0.18–0.66; P = 0.001) and severe IVH (OR 0.39; 95 % CI 0.19–0.82; P = 0.01). In clinical chorioamnionitis (4 studies), antenatal steroids were associated with reduced severe IVH (OR 0.29; 95 % CI 0.10–0.89; P = 0.03) and PVL (OR 0.35; 95 % CI 0.14–0.85; P = 0.02). It was concluded that antenatal steroids may be safe and reduce adverse neonatal outcome after preterm birth associated with chorioamnionitis. There is a need for randomised clinical trials to address this issue.
In the situation of PIH and diabetes, all fetuses at risk of being delivered preterm should be offered the benefits of a single course of antenatal steroids. Several large trials (Crowther et al. 2006; Guinn et al. 2001; Murphy et al. 2008; TEAMS Trial; Wapner et al. 2006) have been developed in recent years comparing single versus multiple courses. The benefits of repetitive courses of corticosteroids may be real, but they seem to be modest relative to the potential for adverse outcomes. A Cochrane review on repeat doses of prenatal corticosteroids concluded that ‘Repeat dose(s) of prenatal corticosteroids reduce the occurrence and severity of neonatal lung disease and the risk of serious health problems in the first few weeks of life. These short-term benefits for babies support the use of repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth. However, these benefits are associated with a reduction in some measures of weight, and head circumference at birth, and there is still insufficient evidence on the longer-term benefits and risks’ (Crowther and Harding 2007). Similar conclusions were reported by a recent review (Bevilacqua et al. 2010).
In low-resource settings, the cost of surfactant still remains very high and unaffordable for most patients. In sharp contrast, antenatal steroids are very cheap as well as effective in preventing RDS. Use of antenatal corticosteroids has benefits beyond their effects on the fetal lung. Preterm infants exposed to antenatal steroids have better transition at birth, higher blood pressures, better renal function and decreased risk of IVH and NEC. Further, antenatal corticosteroids act synergistically with surfactant treatment to improve outcomes – better responses to surfactant therapy, including improved compliance, better gas exchange and less lung injury with ventilation. Several studies have found that either treatment was better than no treatment, and both treatments acted synergistically (Farrell et al. 1989).
32.1.2 Surfactant Replacement Therapy
Surfactant is a mixture of phospholipids, neutral lipids and specific proteins and is synthesised and secreted by type II epithelial cells. The main function of surfactant is to reduce surface tension and prevent alveolar atelectasis. Phospholipids are responsible primarily for the surface tension-lowering activity, but other low molecular weight surfactant proteins (SPs) like the hydrophobic SP-B and SP-C enhance the biophysical activity of phospholipids (Whitsett and Weaver 2002). Three kinds of surfactants are generally available: animal-derived surfactants (natural surfactants), which are extracted from either minced lungs or lung lavage and have high phospholipid concentration and contain the proteins SP-B and SP-C; first-generation synthetic surfactants (artificial surfactant), which do not have surfactant proteins; and newer synthetic surfactants – containing recombinant surfactant proteins or synthetic peptides whose structure and properties resemble that of SP-B or SP-C (Ghodrat 2006). Three approaches have been used to administer surfactant: prophylactic (treatment within the first minutes after birth, usually by 15–30 min, before onset of respiratory symptoms), early rescue (treatment within 2 h, when signs of respiratory distress are present) or late rescue (treatment after 2 h).
Surfactant replacement therapy (SRT) for RDS is a major breakthrough in neonatal medicine that has revolutionised the survival of premature infants with RDS over the last two decades (Fujii and Carillo 2009). It is one of the most well-studied therapies in newborns; more than 40 trials have enrolled almost 10,000 infants and demonstrated a consistent and impressive reduction in neonatal mortality, considering all types of surfactants and all types of approaches (Halliday 2005). Surfactant decreases the need for ventilatory support and complications such as air leaks and improves survival in infants with RDS between 24 and 34 weeks’ gestation (Engle 2008; Soll and Ozek 2010; Seger and Soll 2009). The effect is significantly greater in infants less than 30 weeks’ gestation with birth weight <1,250 g. Because the increase in survival is observed mainly among extremely premature infants, the incidence of CLD has not reduced dramatically despite the widespread use of surfactant. Numerous Cochrane reviews are available looking at various aspects of surfactant therapy – prophylactic use of protein-free synthetic surfactants or animal surfactants, rescue use of surfactants, multiple versus single dose of surfactant, etc. Prophylactic administration of protein-free synthetic surfactants resulted in a decrease in the risk of pneumothorax (RR 0.67, 95 % CI 0.50, 0.90), pulmonary interstitial emphysema (RR 0.68, 95 % CI 0.50, 0.93) and neonatal mortality (RR 0.70, 95 % CI 0.58, 0.85). No differences were seen in the risk of IVH, NEC, BPD, ROP and cerebral palsy. There was an increase in the risk of PDA (RR 1.11, 95 % CI 1.00, 1.22) and an increase in the risk of pulmonary haemorrhage (RR 3.28, 95 % CI 1.50, 7.16) (Soll and Ozek 2010). A review of 13 randomised controlled trials of treatment of established RDS with animal-derived surfactant showed a significant decrease in the risk of any air leak (RR 0.47, 95 % CI 0.39, 0.58), pneumothorax (RR 0.42, 95 % CI 0.34, 0.52), pulmonary interstitial emphysema (RR 0.45, 95 % CI 0.37, 0.55), neonatal mortality (RR 0.68, 95 % CI 0.57, 0.82), risk of mortality prior to hospital discharge (RR 0.63, 95 % CI 0.44, 0.90) and BPD or death at 28 days of age (RR 0.83, 95 % CI 0.77, 0.90). No differences are reported in the risk of PDA, NEC, IVH, BPD or ROP (Seger and Soll 2009). An updated Cochrane systematic review of prophylactic vs selective surfactant was published in 2012 (Rojas-Reyes et al. 2012). The combined overall results did not show any benefit of prophylactic surfactant. A meta-analysis of studies conducted in 1990s when routine early application of CPAP was not practiced revealed decrease in mortality and incidence of air leaks. However, a meta-analysis of two recent large trials in an era of high antenatal steroid use and which applied routine early CPAP found a trend towards increased mortality or CLD with the use of prophylactic surfactant. In general, earlier administration of surfactant results in improved outcomes. OSIRIS trial reported a drop in mortality by 16 % if the time to give surfactant was reduced from 3 to 2 h (The OSIRIS Collaborative Group 1992). One method to reduce the time lag in administering surfactant is to use ‘click test’ (Osborn et al. 2000). Use of the click test in ventilated infants of <28 weeks’ gestation resulted in a 39 % reduction in use of surfactant compared with rescue therapy based on clinical and early chest radiograph diagnoses of RDS. Several large clinical trials have demonstrated that early rescue surfactant therapy also significantly improves survival and reduces complications in RDS and is highly cost-effective. The meta-analysis of 2 trials of multiple- versus single-dose animal-derived surfactants in infants with established RDS suggests a reduction in the risk of pneumothorax (RR 0.51, 95 % CI 0.30, 0.88) and a trend toward a reduction in the risk of mortality (RR 0.63, 95 % CI 0.39, 1.02). One study of multiple- versus single-dose synthetic surfactant in infants at high risk of RDS reported a decrease in NEC (RR 0.20, 95 % CI 0.08, 0.51) and mortality (RR 0.56, 95 % CI 0.39, 0.81). No data on long-term neurological or pulmonary outcome were reported. No complications associated with multiple-dose treatment were reported in the identified trials. The authors concluded that the ability to give multiple doses of surfactant to infants with ongoing respiratory insufficiency leads to improved clinical outcome and appears to be the most effective treatment policy (Soll and Ozek 2009).
In summary, synthetic surfactants without surfactant proteins are inferior to animal-derived surfactant preparations. The data regarding the relative efficacy of the various animal-derived surfactants is limited, but there is a trend favouring surfactant preparations with higher concentrations of phospholipids and surfactant proteins. A higher initial dose of phospholipids may also be important, especially for preterm infants less than 32 weeks of gestation (Fujii and Carillo 2009).
Majority of infants who receive surfactant may be manageable on CPAP, and surfactant may be administered by INSURE technique (INtubate, give SURfactant and Extubate to CPAP within 3–5 min) (Stevens et al. 2007). Another similar study reported success with INSURE in babies between 23 and 29 weeks with 60 % being managed with INSURE, 16 % NCPAP alone and only 24 % receiving MV (Dani et al. 2010). INSURE technique has the advantage of delivering surfactant into the lungs effectively, yet minimising the duration of intubation. However, even short duration of endotracheal intubation can initiate the inflammatory cascade leading to BPD. In addition, the risks and complications associated with pre-medication and intubation are well known. Therefore, minimally invasive or non-invasive methods of surfactant delivery like intrapartum pharyngeal instillation, laryngeal mask airway, feeding or vascular catheters and aerosolization are being explored (Lopez et al. 2013).
32.1.2.1 Comparison of Surfactants
At the present time, beractant (Survanta®), calfactant (Infasurf®) and poractant alpha (Curosurf®) are the three commonly used natural surfactants worldwide. They are available in different concentrations and packing sizes. There are very few head-to-head comparisons between different surfactant preparations in the market. All of them work efficiently and there is little to choose between them. In the developing world, since the family has to purchase the surfactant, the choice of the surfactant is often determined by the weight of the baby and the packing sizes available so that the most economical one is used. Ramanathan et al. demonstrated that treatment with double dose of poractant alpha (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with the need of fewer additional doses of surfactant and significantly reduced mortality as compared to either beractant or poractant alpha (100 mg/kg dose) in infants ≤32 weeks’ gestation with RDS (Ramanathan et al. 2004). Treatment with poractant (Curosurf) when compared to beractant (Survanta) was associated with faster weaning of supplemental oxygen, PIP and MAP during the first 24 h after treatment (Speer et al. 1995). In a meta-analysis of results, mortality was significantly lesser (OR 0.35, CI 0.13–0.92) with poractant alpha. The beneficial effects of poractant over beractant have also been reported in preterm infants ≤29 weeks in a recent study by Fujii et al. (2010). These differences in outcome may be due to differences in composition in terms of phospholipids, SP-B content, antioxidant phospholipids, plasmalogens and anti-inflammatory properties.
Newer synthetic surfactants such as lucinactant (Surfaxin®, Discovery Laboratories, USA) contain protein B mimic synthetic peptide, sinapultide. They can avoid the disadvantage of potential exposure to animal-borne infectious agents or animal proteins that could induce an immune response in fragile premature infants (Lal and Sinha 2008). Prophylactic use of lucinactant has been shown to be more effective than colfosceril (synthetic surfactant) in reducing the incidence of RDS (39 % vs. 47 %). However, there was no difference when compared to beractant (Survanta®). Sinha et al. reported that lucinactant and poractant alpha were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants (Sinha et al. 2005). The Cochrane review on protein-containing synthetic surfactant versus animal-derived surfactant extract for the prevention and treatment of respiratory distress syndrome (two trials) reported no statistically significant clinical differences in death, other outcomes and CLD (Pfister et al. 2009).
It is known that even a short period of intubation can initiate the cascade of events leading to CLD. Yet, as of now, endotracheal tube is the standard route of administration of SRT. The superiority of endotracheal tube with side port for surfactant administration (without need for disconnection from ventilator) over direct instillation into the endotracheal tube is debatable. Other routes, like laryngeal mask airway (LMA), intra-amniotic instillation and nebulisation, are experimental at present (Trevisanuto et al. 2005; Mazela et al. 2007; Donn and Sinha 2008; Abdel-Latif et al. 2010).
Usually, surfactant should be administered in experienced intensive care units having the equipment and personnel to anticipate, recognise and treat complications. It is realised that surfactant therapy is only one part of the comprehensive care of premature infants. The importance of adequate infrastructure, asepsis and meticulous nursing care to optimise survival in surfactant-treated infants has always been stressed. However, SRT may have a role in level II units prior to transport to a specialised NICU. In Israel, very low birth weight outborn infants were shown to have an outcome comparable with that of inborn babies if adequate perinatal care including surfactant administration was provided prior to transportation to a tertiary centre (Arad et al. 2006). Others have shown longer hospital stay and longer duration of ventilation if surfactant was given pre-transport (Costakos and Allen 1996).
32.1.2.2 Status in Developing Countries
In the initial years, surfactant was very expensive and available only in the smuggled market in some developing countries resulting in very restricted use. With the licensing of surfactant import and increasing volumes of usage, the prices of surfactant have decreased by more than half over the last decade, and currently it may be priced lower than that in the developed countries. However, since families themselves have to bear the cost in most situations, less than 50 % of the population may be able to afford it. In view of the huge needs, efforts are ongoing to manufacture the surfactant locally and reduce the costs by another two-thirds. The data from developing countries is however limited. Virtually all of the trials have been done in developed countries. It can be debated whether babies from developing countries who are more likely to be asphyxiated, malnourished and have concomitant infections would respond in similar manner as their counterparts from developed countries. A study by Narang A et al. showed that SRT reduced mortality in Indian babies and was cost-effective in terms of reducing duration of ventilation and hospital stay. It decreased morbidity as the incidence of sepsis and chronic lung disease was lower in babies who received surfactant (Narang et al. 2001). Similar experiences have been reported from Korea (Bae and Hahn 2009).
32.1.2.3 Expanding Use of Surfactant in Newborns
Apart from RDS, qualitative or quantitative deficits of surfactant are often involved in the pathogenesis of various respiratory disorders in late preterm and term babies, including meconium aspiration syndrome (MAS), pneumonia, congenital diaphragmatic hernia (CDH) and inherited disorders of surfactant metabolism involving mutations in the SP-B and SP-C genes (Lacaze-Masmonteil 2007; Whitsett 2006). Preterm infants who have or do not have initial RDS may also exhibit a secondary surfactant deficiency during the course of chronic lung disease or after an acute episode of lung injury such as aspiration, pulmonary haemorrhage or pneumonia. All these disorders may represent potential targets for surfactant therapy.
32.1.2.4 Meconium Aspiration Syndrome (MAS)
The pathophysiologic mechanisms of hypoxaemia in MAS include surfactant dysfunction or inactivation. The hydrophobic chloroform-soluble fraction of meconium is the most potent inhibitor of surfactant function in vitro and in vivo in a dose-dependent fashion (Dargaville et al. 2001). The inhibiting effect of meconium on surfactant function can be overcome by increasing the concentration of surfactant. Synthetic surfactant preparations containing recombinant or analog peptides are more resistant to meconium in vitro than natural animal-derived surfactant (Herting et al. 2001). In animal models of MAS, bolus administration of surfactant is associated with an improvement in mechanical properties, gas exchange, lung inflammation and histology (Hilgendorff et al. 2006). Three randomised controlled trials have shown some benefits of the administration of several boluses of a natural surfactant in the treatment of MAS (Findlay et al. 1996; Lotze et al. 1998; Soll and Dargaville 2007; Chinese Collaborative Study Group for Neonatal Respiratory Diseases 2005). Although there was no difference in mortality in any of these trials, the administration of multiple doses of a natural surfactant was found to improve oxygenation in all, to reduce the need for extracorporeal membrane oxygenation (ECMO) in two and to reduce the risk of pneumothorax in one. In contrast to RDS treatment, where only one dose usually is sufficient to improve oxygenation and permit extubation, long-lasting improvement in oxygenation usually was seen only after at least the second bolus, supporting the need of repeated doses 6 h apart to overcome ongoing surfactant inactivation in infants who have MAS (Findlay et al. 1996; Lotze et al. 1998; Soll and Dargaville 2007). The need to titrate the ongoing inhibiting activity of meconium may account for the improved compliance observed after continuous infusion of surfactant over 1 h compared with bolus administration in a rabbit model of MAS (Robinson and Roberts 2002). In this respect, by removing meconium, inflammatory cells, oedema fluid and surfactant inhibitors from the alveolar space, bronchoalveolar lavage with dilute animal-derived or protein-containing artificial surfactant may be a promising approach for the treatment of severe MAS. This method was also evaluated in the treatment of severe MAS in an open and a small randomised controlled pilot study (Lam and Yeung 1999; Wiswell et al. 2002). In the latter trial, 25 infants who had severe MAS were submitted to a series of bronchoalveolar lavages with dilute lucinactant. A trend toward a more rapid improvement in oxygenation and a shorter duration of mechanical ventilation was observed in the treated group. However, 20 % of the subjects had the procedure abandoned because of hypoxaemia or hypotension. Based on these results, phase 3 clinical trials have been initiated to assess the efficacy and the safety of bronchoalveolar lavage with dilute lucinactant or beractant in severe MAS. Although so far it has not been approved specifically for this disorder by any regulatory agency, surfactant therapy using bolus administration seems to be effective in the management of MAS. Since MAS can have varied pathophysiologic mechanisms of which surfactant deficiency is only one, an approach may be to judge the lung volume clinically or radiologically and use surfactant if the picture is like RDS. In the developing world, use of SRT for MAS may be a very expensive proposition in view of the bigger weight of these babies and the need for multiple doses. The optimal method of administration (lavage or bolus), preparation (natural or peptide-containing synthetic preparation), dosing and time in the course of the disease when surfactant should be given remain to be determined.
32.1.2.5 Late Preterm RDS
Most of the evidence for the benefit of surfactant has come from investigations performed in low or very low birth weight babies. Although RDS is rare in late preterm infants (34–36 weeks), it remains a concern because this population represents 75 % of all preterm births (Jain and Eaton 2006). Lack of clearance of lung fluid, relative surfactant deficiency and secondary inhibition of surfactant function are the major pathophysiologic mechanisms of respiratory distress in late preterm babies. No study has yet specifically evaluated the benefit of surfactant treatment in this population.
32.1.2.6 Pneumonia
In neonatal pneumonia, surfactant may be inactivated by plasma-derived proteins, blood components present in the alveolar spaces (haemoglobin, fibrinogen and immunoglobulins) and by phospholipases released by bacteria. The alveolar epithelium responsible for the synthesis and secretion of surfactant may be injured. In a retrospective review of a large series of preterm and term infants who had respiratory failure associated with GBS sepsis, improved oxygenation and decreased ventilatory requirements were observed after administration of natural surfactant (Herting et al. 2000). SP-A and SP-D, two complex glycoproteins present in pulmonary surfactant, play a major role in the lung defence barrier against pathogenic organisms (Sano and Kuroki 2005). It is hypothesised that SP-A- or SP-D-enhanced surfactants might be beneficial in the treatment of pulmonary inflammation due to infectious diseases (Kingma and Whitsett 2006). The role of SRT in Gram-negative pneumonias has not been studied.
32.1.2.7 Pulmonary Haemorrhage
Haemoglobin and plasma proteins, such as fibrinogen, which are released in alveolar spaces after haemorrhage are powerful inhibitors of endogenous surfactant (Kobayashi et al. 1991). This process may be reversed by increasing the surfactant/inhibitor ratio in the alveolar spaces, like in case of MAS. The administration of an animal-derived surfactant in infants who have pulmonary haemorrhage has been shown to improve the oxygenation index and lung compliance in two uncontrolled reports (Pandit et al. 1995a; Amizura et al. 2003). Improvements generally were immediate and long-lasting. Treatment with exogenous surfactant may be a reasonable option in compromised infants who have severe pulmonary haemorrhage, and further trials are warranted.
32.1.2.8 Congenital Diaphragmatic Hernia (CDH)
In animal models of CDH, it has been shown that surfactant deficiency may be associated with pulmonary hypoplasia and pulmonary hypertension. Few controlled and small-sized studies suggested modest clinical improvement after surfactant administration (Glick et al. 1992). The only but small randomised trial of 17 patients published thus far does not show clinical benefit (Lotze et al. 1994). Retrospective analyses of a large series of treated patients also fail to support any benefit for the use of surfactant therapy in term babies who have CDH (Lally et al. 2004; Van Meurs et al. 2004).
32.1.2.9 Chronic Lung Disease
Surfactant function and contents of SP-A, SP-B and SP-C are altered in mechanically ventilated very preterm babies who experience episodes of lung infection or deterioration. A significant but transient improvement in oxygenation after administration of beractant has been reported in a small number of babies who had stable chronic lung disease and were on mechanical ventilation (Pandit et al. 1995b). The role of intermittent repeated doses of surfactant during the course of chronic lung disease or specifically during episodes of respiratory decompensation needs investigation.
32.1.3 Pulmonary Vasodilators
32.1.3.1 Inhaled Nitric Oxide (iNO)
Numerous pulmonary vasodilators have been tried in the past to treat persistent pulmonary hypertension in the newborn (PPHN), but because of inconsistent effects and serious side effects, they are not used routinely. iNO, which is a potent selective pulmonary vasodilator, has been a great success in comprehensive multicentre trials. iNO along with assisted ventilation is currently the mainstay of therapy of PPHN in the developed world. A Cochrane meta-analysis found 14 eligible randomised controlled studies in term and near-term infants with hypoxia comparing iNO to control with or without backup treatment (Finer and Barrington 2006a). iNO improved outcome in hypoxaemic term and near-term infants by reducing the incidence of the combined endpoint of death or need for ECMO. The reduction was entirely due to a reduction in need for ECMO; mortality was not reduced. Oxygenation improved in approximately 50 % of infants receiving iNO. The oxygenation index decreased by a (weighted) mean of 15.1 within 30–60 min after commencing therapy, and PaO2 increased by a mean of 53 mmHg. The outcome of infants with diaphragmatic hernia was not improved; rather there was a suggestion that outcome was slightly worsened. The incidence of disability, incidence of deafness and infant development scores were similar between tested survivors who received nitric oxide or not. The authors concluded that it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia (Finer and Barrington 2006a). Another Cochrane review for use of iNO in preterms found 14 randomised controlled trials (Barrington and Finer 2010). The trials were grouped post hoc into three categories depending on the entry criteria: entry in the first 3 days of life based on oxygenation criteria, routine use in intubated preterm babies and later enrolment based on an increased risk of BPD. The usefulness of the overall analyses was considered limited by the differing characteristics of the studies, and only subgroup analyses were performed. Nine trials of early rescue treatment of infants based on oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD. The subgroup of three studies with routine use of iNO in intubated preterm infants did not demonstrate significant reduction in the combined outcome of death or BPD (typical RR 0.93 (95 % CI 0.86, 1.01)). Later treatment with iNO based on the risk of BPD demonstrated no significant benefit for this outcome. There was no clear effect of iNO on the frequency of all grades of IVH or of severe IVH. Early rescue treatment was associated with a nonsignificant 20 % increase in severe IVH. No effect on the incidence of neurodevelopmental impairment was found. The authors concluded that iNO as rescue therapy for the very ill preterm infant does not appear to be effective. Early routine use of iNO in preterm infants with respiratory disease does not affect serious brain injury or improve survival without BPD. Later use of iNO to prevent BPD might be effective but requires further study. A recent systematic review found a 7 % reduction in the risk of the composite outcome of death or BPD at 36 weeks for preterm infants treated with iNO compared with controls but no reduction in death alone or BPD and concluded that there is currently no evidence to support the use of iNO in preterm infants with respiratory failure outside the context of rigorously conducted randomised clinical trials (Donohue et al. 2011). The NIH Consensus Development Conference also stated that the combined evidence from the 14 randomised controlled trials of iNO treatment in premature infants of ≤34 weeks’ gestation shows only equivocal effects on pulmonary outcomes, survival and neurodevelopmental outcomes (Cole et al. 2011).
All trials of iNO in term and preterm neonates have been conducted in the developed world. Not only the equipment is expensive, the continuing costs of medical grade iNO are even higher. Anecdotal experience has been reported from some centres (Goh et al. 2001).
32.1.3.2 Phosphodiesterase Inhibitors
Nitric oxide gas is very expensive and not easily available in most developing countries. In addition 30 % of patients of PPHN do not respond to iNO. Hence, there is an ongoing exploration for alternatives. High concentrations of phosphodiesterases in the pulmonary vasculature have led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone. A Cochrane review identified two small eligible trials (Shah and Ohlsson 2007). The total number of enrolled patients in the two studies was 37. Both studies were performed in resource-limited settings where iNO and high-frequency ventilation are not available. Both studies reported statistically significant improvement in oxygenation (reduction in oxygenation index) in the sildenafil group. One study reported a strongly protective effect on mortality (RR 0.17, 95 % CI 0.03, 1.09) favouring the sildenafil group. However, this result needs to be replicated in larger studies. No clinically important side effects were reported. The authors concluded that the safety and effectiveness of sildenafil in the treatment of PPHN have not yet been established and its use should be restricted within the context of randomised controlled trials. However, since sildenafil is cheap and easily available and can even be given orally, it is used very frequently in the developing world. A recent randomised controlled trial allocated 34 infants to MgSO (RCOG 1996) and 31 infants to sildenafil group (Uslu et al. 2011). The time to reach the adequate clinical response (defined as oxygenation index (OI) of <15, a pulmonary artery pressure of <20 mmHg), duration of mechanical ventilation and number of the patients requiring inotropic support were significantly lesser in the sildenafil group.
32.1.3.3 Other Drugs for PPHN
32.1.3.3.1 Magnesium Sulphate
Magnesium sulphate is very cheap and ubiquitously available. Apart from vasodilatory effects, it also acts as a sedative. Because it is low cost and easy to administer, it is commonly used in the developing countries though the effects are not consistent. Hypotension is a serious concern but can be easily tackled with inotropes. A case series of eight newborns was reported from Saudi Arabia (Daffa and Milaat 2002). The babies were given MgSO4 8 % dilution in a loading dose of 200 mg/kg, followed by a maintenance dose of 20–100 mg/kg/h with the aim to keep magnesium levels 3.5–5.5 mmol/L. Seven out of 8 patients showed marked improvement in partial pressure of oxygen at 6 h and maximum improvement at 24 h. A case series of 12 infants who were given magnesium in a similar protocol was reported from Brunei over a period of 2 years (Chandran et al. 2004). Dopamine was commenced at 5–10 μg/kg/min before the loading dose of MgSO4 was given. Mean blood pressure was maintained with short periods of dopamine alone or in combination with dobutamine. Oxygenation index (OI) and alveolar-arterial oxygen gradient (A-aDO2) showed significant improvement within 24 h of treatment. In a recent randomised controlled trial, term infants with PPHN on high-frequency oscillatory ventilation (HFOV) were treated with either iNO or intravenous magnesium sulphate (Boo et al. 2010). Infants in the MgSO4 group (n = 13) were loaded with MgSO4 200 mg/kg infused over half an hour, followed by continuous infusion at 50–150 mg/kg/h to attain a serum magnesium level of 5.0–7.0 mmol/L. Infants in the iNO group (n = 12) were administered nitric oxide at an initial concentration of 20 ppm. There was no significant difference in the proportion of infants who responded primarily to either vasodilator (MgSO4 23 %, iNO 33 %, P = 1.0). After switching over to iNO following a failed MgSO4 therapy, a significantly higher proportion (9 out of 10) of the nonrespondents in the MgSO4 group recovered from PPHN and survived compared to the nonrespondents in the iNO group (1 out of 8) who switched over to intravenous MgSO4 (P < 0.03).
32.1.3.3.2 Milrinone
Milrinone, a phosphodiesterase (PDE) III inhibitor, is routinely used in paediatric cardiac intensive care units to improve inotropy and reduce afterload. Nine full-term neonates with severe PPHN (defined as oxygenation index [OI] >20, failure of iNO therapy and echocardiographic confirmation of PPHN) received intravenous milrinone (McNamara et al. 2006). Intravenous milrinone was commenced at a median age of 21 h, and patients were treated for median of 70 h. Oxygenation index was significantly reduced after milrinone treatment, particularly in the immediate 24 h of treatment. Infants who received milrinone did not develop systemic hypotension; in fact, there was a nonsignificant trend toward improved blood pressure. Another study reported four cases with severe PPHN treated with a combination of iNO and milrinone (Bassler et al. 2006). All four cases were unresponsive to therapy including iNO, with a mean oxygenation index (OI) of 40 before milrinone. Substantial improvement in OI was followed by extubation and survival. However, of 4 patients, 2 developed serious intraventricular haemorrhages (IVHs), and 1 had a small IVH.
32.1.3.3.3 Adenosine
Adenosine infusion causes selective pulmonary vasodilation in fetal and neonatal lambs with pulmonary hypertension. Six consecutive cases of PPHN were treated with adenosine following failure of conventional therapy, excluding iNO (Patole et al. 1998). A rise in arterial PO2 >20 mmHg occurred in 5 of 6 cases within 30 min of commencing adenosine infusion. Individual maximal increases in PaO2 ranged from 31 to 131 mmHg. Three neonates survived and 3 died. Among deaths, intensive support was withdrawn in a preterm neonate due to severe arthrogryposis/pulmonary hypoplasia. Of the remaining two, the improvement in oxygenation persisted until death occurred from causes unrelated to adenosine. Side effects related to adenosine (bradycardia, hypotension, prolonged bleeding time) did not occur. Due to its ease of availability, administration and extremely short half-life, adenosine may be an important therapeutic option in PPHN. In a randomised, placebo-controlled, masked trial comparing the efficacy of 25–50 µg/kg/min intravenous infusion of adenosine to normal saline infusion over a 24 h period, 18 term infants with PPHN and arterial postductal PO2 of 60–100 Torr on inspired O2 concentration of 100 % and optimal hyperventilation (PaCO2 <30 Torr) were enrolled (Konduri et al. 1996). Four of nine infants in the adenosine group and none of the placebo group had a significant improvement in oxygenation, defined as an increase in postductal PaO2 of ≥20 Torr from pre-infusion baseline. Arterial blood pressure and heart rate did not change during the study in either group. The need for extracorporeal membrane oxygenation, incidence of bronchopulmonary dysplasia and mortality were not different in the two groups.
32.1.4 Corticosteroids
32.1.4.1 Systemic Steroids
32.1.4.1.1 RDS
Since antenatal steroids have been shown to be very useful in preventing and decreasing the severity of RDS, it was postulated that postnatal steroids started very early may be able to ameliorate the severity of RDS. Early (<12 h) postnatal dexamethasone therapy of varying duration from 3 days to 3 weeks has been shown to reduce pulmonary inflammation, oxygen requirements, duration of ventilation and a trend to reduce CLD (Lin et al. 1999; Mukhopadhyay et al. 1998). However, steroids need time to induce the synthesis and secretion of surfactant, and the damage due to oxygen and ventilation usually takes place before steroids can have full-blown effects. In addition, there are serious concerns about adverse neurodevelopmental effects of early postnatal steroids as discussed in subsequent section. Hence, early postnatal steroids are not recommended for management of RDS.
32.1.4.1.2 CLD
Systemic steroids have been used early (<96 h of age) or moderately early (7–14 days) to prevent CLD. In addition, they have used late or delayed (>3 weeks of age) to treat CLD. Both early and moderately early approaches reduce the incidence of CLD at 28 days of life and 36 weeks’ PMA (Halliday et al. 2003a, b). Moderately early steroids also reduce mortality at 28 days of age but early steroids do not (Halliday et al. 2003b). Although these benefits are achieved, there are serious side effects – hypertension, hyperglycaemia, gastrointestinal bleed, hypertrophic cardiomyopathy and infections (Committee on Fetus and Newborn 2002). Even more worrisome are increased incidence of cerebral palsy and neurodevelopmental delay reported in trials of early systemic steroids (Halliday et al. 2003a; Committee on Fetus and Newborn 2002). Limited information is available about the long-term follow-up of babies who received moderately early steroids. This has not shown any increase in adverse neurological outcomes (Halliday et al. 2003b). Delayed use of steroids causes lesser side effects but is also less effective showing no effects on mortality and minimal decrease in incidence of CLD at 36 weeks’ PMA (Halliday et al. 2009a, b). Delayed use of steroids has also been linked with hypertension and neurological abnormalities. Because of the serious short- and long-term side effects, the American Academy of Pediatrics has recommended that steroids should not be routinely used in the prevention or treatment of CLD (Committee on Fetus and Newborn 2002).
32.1.4.1.3 Meconium Aspiration Syndrome
Since meconium induces a strong inflammatory response in the lungs, steroids could have potential benefit in MAS. Two small randomised controlled trials, however, have shown no improvement in survival, oxygen dependency at 28 days, duration of ventilation, air leaks or duration of hospitalisation (Wu et al. 1999; Ward and Sinn 2003). Rather, the duration of oxygen was more in those who received steroids.
32.1.4.1.4 Inhaled Steroids for CLD
It was thought that inhaled steroids by virtue of being directly delivered into the lungs in smaller doses may be more effective and have fewer systemic side effects. However, a Cochrane review of three trials conducted in ventilator-dependent preterm babies found no evidence that inhaled corticosteroids confer any advantages over systemic corticosteroids. There was no evidence of difference in effectiveness or side effect profiles for inhaled versus systemic steroids. Long-term follow-up data of babies who received inhaled steroids is also not available. The authors concluded that neither inhaled steroids nor systemic steroids can be recommended as standard treatment for ventilated preterm infants (Shah et al. 2007). The lack of effectiveness may be related to inadequacy of delivery systems. Hence, a better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side effects and needs to be tested.
32.1.5 Methylxanthines
This group of drugs which includes aminophylline, theophylline and caffeine has been used for years in the prevention and treatment of apnoea of prematurity and to prevent extubation failure. In a systematic review of 192 infants from five trials, there was a reduction in recurrent apnoea and the use of mechanical ventilation in the first 2–7 days of methylxanthine use (Skouroliakou et al. 2009). Caffeine is a better drug because of its wide therapeutic index and once a day dosage. It is at least as effective as aminophylline and may be even more effective in the first week of life (Henderson-Smart and Steer 2001). In a large multi-country double-blind trial involving more than 2,000 infants of 500–1,250 g, which compared caffeine to placebo, the caffeine group received lesser supplemental oxygen and lesser days of ventilation (Schmidt et al. 2006). The rates of death, ultrasonographic signs of brain injury and necrotising enterocolitis did not differ significantly between the two groups. Even more reassuringly, the rates of death or neurodevelopmental disability at 18–21 months’ corrected age were significantly lower in the caffeine group (Schmidt et al. 2007). This trial has led to widespread use of prophylactic caffeine in very low birth weight babies. In the developing world, caffeine is not easily available and is expensive, especially in view of its short shelf life. However, local pharmacies can often prepare caffeine solution from pharmacologic grade powder of caffeine. A Cochrane meta-analysis of six trials to study the prophylactic use of methylxanthine treatment for successful extubation observed a 27 % absolute reduction in the incidence of failed extubation, especially in babies less than 1,000 g and less than a week old (Henderson-Smart and Davis 2003).
32.1.5.1 Inhaled CO2 for Apnoea
A small randomised controlled study of 42 preterm infants of gestational age 27–32 weeks suggested that inhaled low (0.8 %) CO2 concentrations in preterm infants are at least as effective as theophylline in decreasing the duration and number of apnoeic episodes, have fewer side effects and cause no changes in cerebral blood flow velocity (Al-Saif et al. 2008).
32.1.6 Drugs for Patent Ductus Arteriosus (PDA) Closure
Presence of PDA increases the risk of CLD. Indomethacin has been used traditionally to close the ductus both intravenously and orally with equal success. The largest trial assessing outcomes following prophylaxis with indomethacin, the international Trial of Indomethacin Prophylaxis in Preterms (TIPP), found a significant decrease in the frequency of PDA following indomethacin therapy (Schmidt et al. 2001). The incidence of IVH also decreases with indomethacin. There was, however, no decrease in the incidence of CLD. Indomethacin decreases blood flow to the brain, kidneys and gut and can increase the incidence of periventricular leukomalacia, gut injury and renal failure. Ibuprofen, another cyclooxygenase inhibitor, has been shown to be effective in PDA closure without reducing blood flow velocity to the brain, gut or kidneys. A Cochrane meta-analysis included 20 studies and found no statistically significant difference in PDA closure rates between indomethacin and ibuprofen (Ohlsson et al. 2010). The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (RR 0.68, 95 % CI 0.47, 0.99), and there was less evidence of transient renal insufficiency in infants who receive ibuprofen compared to indomethacin. Orogastric administration of ibuprofen was as effective as i.v. administration. Hence, ibuprofen currently appears to be the drug of choice.
32.1.7 Potential Drugs for Prevention and Treatment of BPD
32.1.7.1 Vitamin A
Vitamin A deficiency has been postulated to contribute to development of BPD because of the role of vitamin A in epithelial differentiation and maturation processes. Low serum concentrations of vitamin A in preterm infants have been associated with an increased risk for developing CLD. Tyson et al. reported increased vitamin A levels and reduced incidence of BPD after intramuscular supplementation of vitamin A for 28 days of life (Tyson et al. 1999). However, because of the necessity to give multiple i.m. injections, routine parenteral vitamin A supplementation is not in widespread use (Ambalavanan et al. 2004). Oral regimens have failed to achieve similar results. It remains to be seen whether a combined regimen of parenteral followed by oral vitamin A can be effective.
32.1.7.2 Vitamin E and Antioxidants
Vitamin E – an antioxidant and a scavenger of free radicals – has been extensively studied in preterm neonates. A systematic review of the vitamin E trials indicates that supplementation does not decrease the incidence of CLD (Brion et al. 2003). Superoxide dismutase, an antioxidant, has been tried in two small trials, but no benefit for prevention of CLD could be demonstrated (Rosenfeld et al. 1984; Wiswell et al. 2007).
32.1.7.3 Diuretics
Diuretics like furosemide, thiazides and spironolactone are commonly used in preterm babies with evolving or established CLD. They are used intravenously, orally and as areosolised form. The purpose is to reduce alveolar and interstitial oedema. They, however, have numerous short- and long-term side effects on electrolyte balance, ototoxicity and nephrocalcinosis. Furosemide has been shown to cause short-term improvement in pulmonary functions (Brion et al. 2002). But there are no effects on ventilator settings, duration of ventilation, hospitalisation or mortality. Hence, diuretics should be used very sparingly and only for short duration.
Diuretics have also been tried for acute RDS and transient tachypnoea of newborn but have failed to show any benefits (Brion and Soll 2008).
32.1.7.4 Beta-Agonists
Hyperreactivity of airways is seen in babies with RDS and BPD, especially in those on mechanical ventilation. Salbutamol (albuterol) has been assessed in multiple short-term studies. Variable effects on pulmonary mechanics – improvement, no change or worsening – have been demonstrated in these studies. In a prevention trial in at-risk infants, no effect could be seen on mortality or occurrence of CLD (Denjean et al. 1998). None of the trials of bronchodilators in babies with ventilator dependency has assessed important clinical outcomes like death, CLD at 36 weeks or duration of oxygen (Ng et al. 2001). It is also not easy to deliver the bronchodilator drugs in intubated neonates, and that may be an important factor causing wide variability in responses.
32.1.7.4.1 Other Bronchodilators
Anticholinergic agents like ipratropium bromide and mast cell stabiliser cromolyn Na have been used in case series or small trials of short-term use (Wiswell et al. 2007). Generally, the short-term effects are mixed and long-term effects unknown.
32.1.7.5 Erythromycin
Ureaplasma urealyticum has been commonly isolated from the tracheal secretions of preterm neonates on ventilator and has been implicated in the pathogenesis of CLD (Mabanta et al. 2003). Two small trials have assessed the efficacy of treatment with erythromycin in the prevention of CLD in intubated preterm infants at risk for or colonised with this organism (Jonsson et al. 1998; Lyon et al. 1998). No effect on death or on the development of CLD has been demonstrated in these studies.
32.1.8 Sedatives and Analgesics
32.1.8.1 Opioids
The presence of endotracheal tube and ventilation is painful to the preterm and term newborn. Multiple painful episodes have the potential to impair neurological outcomes and behaviour. However, the use of analgesics and sedatives, especially narcotics, has been problematic because of adverse effects, especially on the developing brain (Durrmeyer et al. 2010). Initial trials suggested that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurological outcomes in preterm neonates who require ventilatory support (Anand et al. 1999). However, large multicentre trials showed that placebo and morphine groups had similar rates of the composite outcome, neonatal death, severe IVH and PVL. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine, while morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (Anand et al. 2004). Hence, though it is realised that ventilated neonates feel pain and narcotic analgesics are effective in reducing pain, there are potential adverse effects on the developing brain which limit the routine use of these drugs (Bellù et al. 2005). These drugs are more commonly used in babies with PPHN or difficult ventilation and asynchrony. Of the two most commonly used opiods, fentanyl causes lesser hypotension but is more expensive and causes chest wall rigidity. Continuous low-dose infusions are better than bolus administrations of both the opioids.
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