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Adjunctive therapies in chronic lung disease: Examining the evidence
Seminars in Fetal & Neonatal Medicine (2008) 13, 44e52
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Adjunctive therapies in chronic lung disease: Examining the evidence Win Tin a,*, Thomas E. Wiswell b a b
The James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK Centre for Neonatal Care, Florida Hospital Orlando, 2718 North Orange Avenue, Suite B, Orlando, FL 32804, USA
KEYWORDS Adjunctive therapy; Chronic lung disease (CLD); Preterm; Respiratory distress syndrome (RDS)
Summary Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) is one of the most common long-term complications in very premature infants. The incidence of CLD has been increasing over the past two decades in parallel with an improvement in the survival of this population. We have witnessed a revolution in the therapies that are used, either to manage these infants’ respiratory distress syndrome (RDS) with an aim to prevent CLD or to manage the established condition. Several devices and strategies have been developed to provide respiratory support with minimal risk of lung injuries. Multiple adjunctive agents have also been used either to reduce the risk of CLD or to mitigate its course. There is considerable evidence supporting the use of exogenous surfactant, but unfortunately many other therapies currently used for CLD, either preventative or as a treatment, are based on very little or no evidence. The gold standard to assess a given therapy is the randomised controlled trial (RCT), designed to look at clinically meaningful outcomes and long-term safety. In this context, we discuss the support e or lack thereof e for the adjunctive therapies used in relation to CLD. Many of the therapies have been examined as systematic reviews by the Cochrane Neonatal Review Group. These reviews are noted in the references and can be easily accessed at the following website sponsored by the National Institute of Child Health and Human Development: www.nichd.nih.gov/ cochrane/default.cfm. Published by Elsevier Ltd.
Introduction Chronic lung disease (CLD) continues to be one of the most common long-term complications associated with preterm birth. Despite improvement in neonatal respiratory care, the incidence of CLD continues to be high, especially as survival of extremely premature infants has improved.
Although the primary pathology of CLD is related to lungs, it is in fact a multisystem disease and, once established, the treatment remains mostly supportive. In this article, we provide the rationale and scientific evidence for the strength and weaknesses of some of the commonly used therapies, which remains mostly individual- or institutionspecific, and hope that this will help clinicians critically to appraise their own practices.
* Corresponding author. Tel.: þ44 (0)1642 854 834; fax: þ44 (0)1642 854 874. E-mail address: [email protected] (W. Tin). 1744-165X/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.siny.2007.09.008
Adjunctive therapies in chronic lung disease
Oxygen therapy Supplemental oxygen is probably the most commonly used therapy in preterm infants who have RDS and CLD, along with other therapeutic adjuncts. The ultimate goal of oxygen therapy is to achieve adequate tissue oxygenation, but without creating oxygen toxicity and oxidative stress. In addition to the inspired oxygen, tissue oxygenation depends upon several other factors, including gas exchange mechanism within the lungs, oxygen-carrying capacity of the blood (approximately 97% of oxygen transported to the tissue is carried by the haemoglobin and 3% is dissolved in plasma), cardiac output and local tissue oedema or ischaemia.1 Therefore, optimising these factors may allow adequate oxygenation with the use of minimal supplemental oxygen. Oxygen was discovered by Priestley, along with Scheele and Lavoisier, in 1774. The experimental work and research carried out over more than a century have shown that like any other ‘drug’, too much oxygen can be toxic and damaging.2 Oxygen toxicity as an important cause of retinopathy of prematurity (ROP) was first described by Campbell,3 and this observation was confirmed by controlled trials more than 50 years ago.4 Direct exposure to high concentrations of oxygen can damage the pulmonary epithelium, and this has also been recognised as an important cause of bronchopulmonary dysplasia (BPD), ever since BPD was first described by Northway et al.5 Even if the inspired oxygen is not high, oxidative stress (defined as an imbalance between pro- and antioxidant forces) can occur, especially in preterm infants who are more vulnerable to the harmful effects of free oxygen radicals.6 Two RCTs have been conducted to see whether it is better to aim for high oxygen saturation in preterm infants who are more than a few weeks old. The American STOP-ROP trial7 which recruited 649 babies with a mean birth gestation of 25.4 weeks showed that keeping fractional oxygen saturation above 95% slightly reduced the number of infants with pre-threshold retinopathy who went on to develop disease severe enough to require retinal surgery. However, benefit was only seen in those without evidence of ‘plus disease’ (dilated and tortuous vessels in at least two quadrants of the posterior pole) at recruitment. More unexpectedly, targeting higher oxygen saturation significantly increased the number of infants who remained in hospital, in supplemental oxygen, and who were perceived to need diuretic therapy at 50 weeks’ post-menstrual age (PMA). The result of the Australian BOOST trial was published in 2003.8 The aim of this double-blind study was to see whether maintaining higher oxygen saturations versus standard levels among oxygen-dependent preterm infants improved their growth and development. This study recruited 358 babies of less than 30 weeks’ gestation who remained in supplemental oxygen at 32 weeks’ PMA. Trial oximeters were specially modified to keep targeted functional saturation in the range of either 91e94% or 95e98%, while displaying a level (masked) in the range 93e96%. This well-designed study showed no evidence that the growth and developmental outcome of oxygen-dependent preterm infants was improved by keeping their oxygen saturation in the high range. In keeping with the observation in the STOP-ROP trial, the BOOST trial
45 also showed that infants in the higher oxygen saturation range showed greater use of postnatal steroids and diuretics, more readmissions and more pulmonary-related deaths. To date, there is insufficient evidence to suggest the optimal oxygen level to be aimed for in preterm infants who receive oxygen therapy in the early neonatal period. The largest cohort study ever carried out showed a strong association between the prevalence, as well as severity, of ROP and the duration of exposure to a transcutaneous oxygen pressure (TcpO2) of more than 80 mmHg (w10.7 kPa),9 but no similar study has ever been mounted as it became commonplace to use pulse oximetry as non-invasive continuous monitoring to guide the oxygen therapy. Most observational studies published recently have suggested that in comparison with the ‘liberal approach’ of attempting to maintain high oxygen saturation values (measured by pulse oximetry), the ‘restrictive approach’ of accepting lower oxygen saturation values was associated with lower incidences of ROP (including severe ROP requiring surgery) and CLD, without the increased risk of mortality.10e13 The follow-up information available from one of these studies showed that the ‘restrictive approach’ of oxygen therapy did not increase the risk of cerebral palsy10 and, more relevantly, it was not associated with any disadvantages in terms of intellectual skills, academic achievements, adaptive functioning and behaviour.14 In contrast, a retrospective analysis of an observational data by Poets et al., involving 891 babies of <30 weeks’ gestation and admitted to two neonatal units, using different oxygen saturation limits (80e92% versus 92e97%), showed that the incidence of ROP (more than stage 2) was significantly higher in the unit that used a lower alarm limit (13% versus 6%), although no difference was seen in the incidence of ROP that required surgery.15 The lack of knowledge and ongoing uncertainty about the ‘optimal’ oxygenation for newborn infants making the transition to extrauterine life has led to wide variation of policies on oxygen-monitoring and therapy in neonatal nurseries.16,17 Observational studies over the past 50 years have got us nowhere, and the only way to resolve the uncertainties and controversies of oxygen-monitoring and therapy is to conduct well-designed RCTs.18 In response to the growing demand to resolve the uncertainty of oxygen therapy in very premature babies, an international collaborative effort has been mounted since 2003, to conduct large, multicentre, masked RCTs to answer the question: What oxygen saturation level should be aimed for in very premature infants? Infants of under 28 weeks’ gestation are eligible for these studies if they are less than 24 h of age; with an international collaborative effort, it is envisaged that a total of over 5000 babies will be enrolled into the ‘oxygen trials’. All these trials will address the principal research question: Does varying the concentration of inspired oxygen to maintain a ‘low’ oxygen saturation range of 85e89% versus a ‘high’ range of 91e95% in babies of less than 28 weeks’ gestation from the day of birth until they are breathing air or until 36 weeks’ PMA affect the incidence of 1. Death or severe neurosensory disability at a corrected age of 2 years? 2. Retinal surgery for ROP?
46 3. The need for supplemental oxygen therapy or respiratory support at 36 weeks’ PMA? 4. Patent ductus arteriosus (PDA) and necrotising enterocolitis? 5. Poor growth at 36 weeks’ PMA and at 2 years? There has already been a prospective agreement to combine the individual patient data from all the trials in order to increase the ability to detect much smaller differences of the primary outcome. This controlled trialstrategy of prospective meta-analysis is likely to be established for the first time in neonatal medicine from ‘the oxygen trials’. Until the uncertainties and controversies on oxygen therapy and its monitoring are resolved, clinicians should follow the words of wisdom by Julius Comroe in 1945: ‘‘The clinician must bear in mind that oxygen is a drug and must be used in accordance with well-recognised pharmacologic principles; i.e., since it has certain toxic effects and is not completely harmless (as widely believed in clinical circles) it should be given only in the lowest dosage or concentration required by the particular patient.’’
Methylxanthine therapy Methylxanthines act by non-specific inhibition of adenosine receptors A1 and A2. Adenosine is involved in the regulation of sleep and arousal, susceptibility to seizures and analgesia. The extracellular concentrations of adenosine in the brain increase when energy demand is more than the supply. An imbalance between ATP synthesis and breakdown results in conditions such as seizures, hypoxia, ischaemia and hypoglycaemia.19 The role of adenosine as a neuromodulator under physiological and pathophysiological conditions is an area of extensive investigation, which is, as yet, incompletely understood. The methylxanthines, aminophylline, theophylline and caffeine, have been used for more than three decades to treat apnoea of prematurity.20 This widespread use of methylxanthines is based entirely on the reports on the short-term outcomes, and until recently, there was no data on the long-term effects including safety. Theophylline has been observed to reduce apnoea by increasing the sensitivity to carbon dioxide21 and improving the minute ventilation.22 The effect on improvement in tidal volume by methylxanthines has been observed to be similar to other stimulants such as 2% CO2 and 100% O2, with little or no change in respiratory frequency.23 There are limited numbers of studies to evaluate the clinical effects of methylxanthine therapy. The results of the meta-analysis for prevention of apnoea in preterm babies by the prophylactic use of methylxanthines,24 or its comparison with doxapram in preventing apnoea,25 do not show any significant benefit. However, in a meta-analysis of 192 infants from five trials, there was a reduction in recurrent apnoea and use of intermittent partial pressure ventilation in the first 2e7 days of methylxanthine use.26 The 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 with the number needed to treat being 3.7 (2.7, 6.7). However, this
W. Tin, T.E. Wiswell benefit was observed in babies under 1000 g and those less than a week old. The advantages were lost if babies were below 1000 g and over 1 week of age, or 1000e1250 g who had failed extubation once.27 Caffeine (usually in the form of caffeine citrate) is now the preferred choice as routine drug monitoring is not necessary because of its wider margin between the therapeutic and toxic levels.28 Schmidt et al. recently reported the short-term outcome ‘at neonatal discharge’ of 2006 preterm infants with a birthweight between 500 g and 1250 g.29 This multicentre double-blind study, known as the CAP (caffeine for apnoea of prematurity) trial, showed that caffeine reduced the duration of supplemental oxygen therapy, continuous positive airway pressure and mechanical ventilation. Treated infants were less likely to have BPD, defined as a need for supplemental oxygen at 36 weeks’ PMA. Unexpectedly, caffeine therapy was also found to be associated with a reduction in the risk of PDA deemed to need pharmacological and surgical closure. This large study also provides some reassurance that caffeine did not increase the risk of neonatal complications, including necrotising enterocolitis and ultrasonographic evidence of brain injuries. Available data on the long-term follow-up of this study also showed that caffeine therapy for apnoea of prematurity improves the rate of survival without neurodevelopmental disability in very low birthweight infants at a corrected age of 18e21 months.30 The CAP trial is one of the best examples of using a ‘gold standard’ to examine the evidence for use of a therapy commonly used in neonatal medicine.
Corticosteroid therapy Systemic and inhalational corticosteroids have been used to prevent or treat CLD in preterm infants. These therapies have been given early (<96 h of age)31 and moderately early (7e14 days of age)32 with the aim of preventing CLD, or delayed/late (>3 weeks of age)33 as treatment for CLD. Both ‘early’ and ‘moderately early’ systemic corticosteroids significantly reduce the incidence of CLD at either 28 days of age or 36 weeks’ PMA. Moderately early treatment was associated with the reduction in mortality through 28 days of age but not thereafter, and there was no reduction in mortality following early treatment. Unfortunately more adverse effects including hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection were observed following both early and moderately early treatments.31,32 More relevantly, in the trials that have reported long-term follow-up information, significantly higher adverse neurodevelopmental outcomes (developmental delay, cerebral palsy, abnormal neurological examinations) were seen following early systemic corticosteroid therapy.31 There was no evidence of an increase in adverse neurodevelopmental outcomes following moderately early treatment with systemic corticosteroids; however, the follow-up data was limited.32 ‘Delayed/late’ systemic corticosteroids had no effect on mortality and had a borderline effect on reducing the incidence of CLD at 36 weeks’ PMA. There was no increase in the occurrence of infection, hyperglycaemia, or gastrointestinal complications,
Adjunctive therapies in chronic lung disease but hypertension was significantly more common with delayed corticosteroid therapy in preterm infants. Although there was an increased rate of abnormal neurological examination among those receiving delayed corticosteroid therapy, there was no increase in the rates of cerebral palsy and major neurosensory disabilities.33 However, information on this long-term outcome is limited. Two systematic reviews of inhalational versus systemic corticosteroids have shown that there was a borderline increase in CLD at 36 weeks’ PMA following the use of inhaled compared to systemic steroids in preventing CLD,34 and that inhaled corticosteroids are no more effective than systemic corticosteroids as treatment in established CLD.35 There is no long-term outcome data available from studies using inhaled corticosteroids to prevent or treat CLD. In view of the concerns about long-term adverse effect on neurodevelopment and short-term side-effects, the Committee on Fetus and Newborn of the American Academy of Pediatrics and Canadian Pediatric Society recommended against the routine use of corticosteroids to prevent or treat CLD.36 However, a recently published double-blind RCT, which had recruited 70 ventilator-dependent infants of less than 28 weeks’ gestation or less than 1000 g to receive either a low-dose dexamethasone or placebo after the first week of life, found that corticosteroid therapy shortened the duration of intubation, without any shortterm complications,37 and showed no obvious long-term harm in terms of neurosensory outcome, blood pressure or hospital readmissions.38 The study was originally designed to detect 10% difference in the rate of survival without major neurosensory disability with an adequate power. However, it was stopped with less than 10% of the target sample size because of very poor recruitment and, therefore, the effect of low-dose dexamethasone on long-term development cannot be conclusive. A meta-regression analysis of 28 RCTs with available follow-up data from 1721 randomised infants showed that the impact of postnatal corticosteroids on the combined outcome of death or cerebral palsy was also modified by the risk of CLD in the control group of infants (Fig. 1).39 Based on the evidence that adverse effects of postnatal corticosteroids may be related to high dose and its early use on infants with relatively lower risk of CLD, clinicians should seriously consider reexamining this potentially powerful therapeutic agent in CLD.
Diuretic therapy Lung oedema and PDA may complicate RDS in preterm infants. These complications, along with renal insufficiency, are the main reasons that furosemide is the most common diuretic used in the early neonatal period. Furosemide is a rapidly acting diuretic on the loop of Henle, inhibiting active reabsorption of chloride and leading to active reabsorption of sodium. In addition, furosemide also has a direct effect on reabsorption of lung fluid and can improve the lung function for a short period. The half-life of furosemide in term infants is about 8 h, but it may be as long as 24 h in preterm infants. Prolonged use increases renal loss of sodium and potassium and also urinary calcium excretion and the risk of renal calcium deposition.
47
Figure 1 Risk difference (RD) % for death or cerebral palsy (CP) among all participants in 14 randomised controlled trials versus rate of chronic lung disease (CLD) in the control group. Each study is shown by a circle whose area is proportional to that study’s weight. Regression line (solid) and its 95%CI (dotted) showed that with risks for CLD below 35%, postnatal corticosteroid therapy significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance (Reproduced with permission from Doyle LW, et al.39).
Early use of furosemide is associated with increased incidence of PDA in preterm infants as it stimulates the production of prostaglandin E2 from the kidneys. Repeated use of this therapy in preterm infants increases the risk of ototoxicity and it can also enhance the risk of aminoglycoside ototoxicity.28 Bumetanide is another ‘loop’ diuretic with a similar mechanism of action, but it is more potent and probably less ototoxic than furosemide. However, it can also cause significant urinary losses of sodium, chloride and calcium and its neonatal use has not been fully evaluated.28 A systematic review of the use of furosemide for RDS in preterm infants has shown that this therapy had no effect on meaningful outcomes, including duration of mechanical ventilation and oxygen supplementation, length of hospitalisation and more relevantly, on mortality and CLD.40 All the six trials included in this review were carried out before the era of antenatal steroid and surfactant replacement therapy, and there is no current evidence to support the routine use of furosemide or any other diuretics in preterm infants who have RDS. The distal tubule diuretic, thiazide, the potassium-sparing diuretic, spironolactone, and the loop diuretic, furosemide, are commonly used in preterm infants who have established CLD. These diuretics are administered parenterally, enterally, or by inhaled aerosol to reduce alveolar and interstitial lung oedema and to improve pulmonary mechanics. A thiazide diuretic, chlorothiazide, is often used in combination with spironolactone for the control of pulmonary oedema in preterm infants with severe CLD, and this is felt to be the safest diuretic combination for long-term use. Chlorothiazide inhibits reabsorption of sodium and chloride from the urine in distal convoluted tubules, thereby increasing the excretion of sodium and subsequently, potassium. Spironolactone is a potassium-sparing diuretic that inhibits the action of aldosterone on distal tubules. Thiazide
48 diuretic in combination with spironolactone can also cause excessive urinary calcium loss and subsequent bone demineralisation and nephrocalcinosis in preterm infants.28 Despite their widespread use, there are surprisingly few data assessing the meaningful value of diuretic therapy in CLD. All the systematic reviews to assess the risks and benefits of furosemide (including aerosolised form) as well as thiazides (with or without spironolactone) in preterm infants with, or developing, CLD have shown improvements in both oxygenation and lung compliance. However, these studies focused on pathophysiological parameters and the findings cannot be translated to the improvement in meaningful outcomes (mortality, duration of mechanical ventilation and oxygen dependency and length of hospital stay).41e43 Of all the adjunctive therapies used in preterm infants with CLD, diuretic therapy is one of the most abused without evidence of substantive benefit.
Inhaled nitric oxide therapy Nitric oxide is a highly diffusible colourless gas produced by many cells in the body including endothelial-lining cells of the blood vessels. Nitric oxide is a potent vasodilator because of its effect as ‘relaxing factor’ on the vessel tone. Inhaled nitric oxide (iNO) can produce potent selective pulmonary vasodilatation without lowering systemic blood pressure as the gas has a very short half-life (2e4 s) in the body,28 which forms the physiological rationale for the clinical use of iNO in newborn infants with pulmonary hypertension. In infants with predominantly intrapulmonary shunting due to atelectasis and ventilation perfusion mismatch, iNO may also improve oxygenation by redirecting blood from poorly aerated or diseased lung regions to better aerated spaces e the ‘micro selective effect’.44 Animal studies have also suggested that iNO reduces lung inflammation,45 improves surfactant function46 and promotes lung growth.47 The initial reports on the benefit of iNO in infants with persistent pulmonary hypertension and hypoxaemic respiratory failure were published in 1992,48,49 and evidence from RCTs have already shown that iNO therapy improved oxygenation and reduced the risk of death or requirement for treatment with extracorporeal membrane oxygenation (ECMO) in respiratory failure in infants born at, or near term (34 weeks’ gestation).50 However, the role of iNO in preterm infants with hypoxaemic respiratory failure, both in terms of its efficacy and safety is less clear and remains controversial.51 The pilot studies on preterm infants with severe CLD have suggested that iNO therapy was safe and was associated with short-term improvement in oxygenation.52,53 However, to date, there are no other clinical data to support the use of iNO in infants with established, severe CLD. Most RCTs in preterm infants with ‘severe’ respiratory failure have shown that iNO did not reduce the risk of death or CLD. A double-blind RCT by Kinsella et al. looking at the efficacy of low-dose iNO (5 ppm) on 80 preterm infants with severe hypoxaemic respiratory failure did not show any differences in the primary outcome measure of ‘survival to discharge’, though there was an observed short-term improvement in oxygenation among treated infants.54 Another multicentre RCT carried out in the UK and the
W. Tin, T.E. Wiswell Republic of Ireland to evaluate the efficacy of iNO in preterm infants (<34 weeks’ gestation) with severe respiratory failure, showed that there was no evidence of an effect of iNO on the primary outcomes: death or severe disability at 1 year corrected age; death or supplemental oxygen on expected date of delivery; or death or supplemental oxygen at 36 weeks’ PMA. Furthermore, this study also showed that ‘mean total costs’ at 1 year corrected age were significantly higher in a group of infants allocated to receive iNO, partly because of the cost of the gas, but mainly because of the difference in initial hospitalisation costs.55 The main drawback of this study was its poor recruitment of only 108 infants despite the planned sample size of 200 infants. A large multicentre study by Van Meurs et al. also showed that iNO has no impact on the risk of death or CLD in preterm infants with a birthweight of <1500 g and with severe respiratory failure. In fact, this study suggested an increased risk of death with iNO therapy amongst infants with a birthweight of <1000 g.56 However, a single-centre study by Schreiber et al. demonstrated that iNO reduced the risk of death and BPD in preterm infants with RDS. Treated infants also had a reduced risk of brain injuries, as evident on ultrasonography, and more relevantly, had a better neurodevelopmental outcome compared to the control group.57 Nonetheless, it is important to note that the rates of CLD and brain injuries were higher than expected in the control group of infants who received oxygen as a placebo. Two recently reported large RCTs have hinted at the potential benefits of iNO in preterm infants with a birthweight between 500 g and 1250 g. Although the mean gestational age of infants was the same in both studies, the age at which iNO was initiated, the dose of iNO and the duration of intervention were considerably different. In the trial by Kinsella et al. (2006), infants who were receiving mechanical ventilation and who were less than 48 h of age were randomly assigned to receive either 5 ppm of iNO or nitrogen as a placebo. This trial did not show a reduction in the overall incidence of CLD by ‘early’ iNO therapy, with the exception of the pre-stratified group of infants with a birthweight between 1000 g and 1250 g (16% of the study group). However, iNO therapy was found to have reduced the incidence of brain injuries in this trial.58 In contrast, the trial by Ballard et al. enrolled infants who were ventilator-dependent (and also infants with a birthweight between 500 g and 799 g who were on continuous positive airway pressure) at 7e21 days. Treated infants received iNO 20 ppm for 48e 96 h, with a dose reduction at weekly intervals. This large trial showed that iNO improved the survival without CLD at 36 weeks’ PMA but this improvement in the primary outcome was only limited to infants who were 7e14 days of age at randomisation. The complications of prematurity, including ultrasonographic evidence of brain injuries, were not different between the two groups.59 Although these two recent studies have suggested that iNO may be of benefit in preterm infants who were less critically ill, and the findings on brain injuries are reassuring, the most effective dose, timing and duration of iNO therapy and the selection of infants most likely to benefit from this therapy remain uncertain. Because iNO is one of the most expensive therapies and there is a lack of long-term follow-up information, the ‘routine’ use of iNO therapy in preterm infants is not justifiable and should be limited to clinical trials.60
Adjunctive therapies in chronic lung disease
Other adjunctive therapies Indomethacin and ibuprofen therapy
49 chemotaxis, and as such could help to regulate the inflammatory processes in the lung. Two small RCTs have been performed to assess the early use of this therapy in preventing CLD.70,71 Both trials showed no difference in mortality or CLD (at 28 days and 36 weeks’ PMA). There has been no RCT to assess cromolyn therapy for established CLD and so also this therapy cannot be recommended in the management of CLD.
PDA is one of the risk factors for CLD in preterm infants.61 Indomethacin, a cyclo-oxygenase inhibitor, has been the mainstay in treating or preventing PDA over the past 25 years.62 It is reasonable to assume that a treatment regimen that prevents PDA should reduce the risk of CLD in this population. The largest RCT to assess the outcomes following the early prophylactic use of indomethacin in very low birthweight infants (International Trial of Indomethacin Prophylaxis in Preterms [TIPP])63 showed a significant reduction in the incidence of PDA following indomethacin therapy. However, there was no reduction in the incidence of CLD, a finding similar to all other RCTs that have assessed this therapy.62 Ibuprofen, another cyclo-oxygenase inhibitor has been shown to be equally effective in PDA closure. Its use is gaining in popularity over the past decade as it does not cause reduction in regional blood flow to the brain, kidneys and gut.28 It has also been assessed in RCTs, with results similar to those seen with indomethacin e neither a significant reduction nor even a trend towards reduction in CLD was observed.64
Vitamin A is involved in the regulation and promotion of growth and differentiation of multiple cells. It also maintains the integrity of respiratory tract epithelial cells. Very preterm infants are relatively deficient in vitamin A, which has been shown to be associated with CLD. A large RCT of 807 infants with a birthweight of less than 1000 g has shown that a large dose of intramuscular vitamin A, given three times a week for 4 weeks from birth, slightly decreased the risk of CLD (OR 0.89; 95%CI 0.8e0.99).72 Other smaller trials have also pointed to a similar conclusion.73 However, this preventative therapy requires several injections. A trial of oral vitamin A therapy daily for 4 weeks in a similar population of infants failed to detect any benefit.74
Beta-receptor agonist therapy
Vitamin E therapy
Bronchodilators, such as beta-receptor agonists, are potentially attractive therapies for preterm infants with CLD, as bronchial hyperactivity and responsiveness may be found in this population, while assisted ventilation may also aggravate the response. One double-blind RCT using inhaled salbutamol (albuterol) and beclomethasone to prevent CLD found no evidence that this therapy reduced mortality, oxygen dependency at 28 days, duration of ventilation and duration of oxygen supplementation in preterm infants.65 Several studies that assessed the immediate changes in pulmonary mechanics (compliance, resistance) following the use of salbutamol66 have shown variable results, including improvement, no change or even worsening in these respiratory parameters. As so far there has been no RCT to review meaningful clinical outcomes following beta-receptor agonist therapy, the usefulness of beta-receptor agonist therapy in treating infants with CLD remains unknown.
Vitamin E consists of several types of tocopherols with antioxidant activity. As a scavenger of free radicals, it could potentially limit the processes that lead to CLD. Vitamin E has been extensively studied in preterm infants with the expectation that it could help prevent oxidative stress-related damage to multiple organs, but a systematic review of the vitamin E trials in this population indicates that this therapy does not reduce the incidence of CLD.75
It was hoped that the antioxidant superoxide dismutase (SOD) could ameliorate oxygen free radical injury to the premature lungs. However, two small RCTs carried out to assess the effect of SOD in preventing CLD76,77 failed to detect any benefit and the use of SOD in preterm infants cannot therefore be recommended.
Anticholinergic therapy
Conclusions
Ipratropium bromide, a muscarinic antagonist, has some effect on bronchodilation and has been used to treat infants with CLD. The data available are limited to case reports following short-term use of this therapy.67e69 Results are mixed with some reports demonstrating positive effects and some indicating either no or negative effects. Without supportive evidence from an RCT, this therapy cannot be recommended in the management of CLD.
CLD/BPD is still one of the most challenging complications in preterm infants, and carries the potential for mortality and major morbidity. As with much of neonatal care, several therapeutic agents have made their way into the prevention and treatment of this very frustrating condition without being assessed adequately for meaningful efficacy and long-term safety. The careful examination of the evidence for many of these adjunctive therapies shows there is very little or no basis to support the routine use of a vast majority of them. We have a moral obligation to our patients and their families to practice evidence-based medicine and to collaborate with each other in examining the evidence for all therapies commonly used in neonatal medicine.
Cromolyn sodium therapy Cromolyn sodium (disodium cromoglycate) is a mast cell stabiliser that also inhibits neutrophil activation and
Vitamin A therapy
Superoxide dismutase therapy
50
W. Tin, T.E. Wiswell
Practice points Among the therapeutic agents used, either to reduce the risk of chronic lung disease (CLD) or to mitigate its course, several of them are based on very little or no evidence. Caffeine therapy in preterm infants not only reduces the risk of CLD, but also improves the rate of survival without neurodevelopmental disability. Oxygen is probably the most commonly used therapy in preterm infants with respiratory disease syndrome and CLD, but to date there is no good evidence to guide us how much oxygen is appropriate to give to these vulnerable infants. Adverse effects of postnatal steroids may be related to high dose and its early use in infants with relatively low risk of CLD. Two recently published randomised controlled trials (RCTs) suggested that inhaled nitric oxide may be of benefit in preterm infants who were less critically ill, but the evidence available to date does not justify its ‘routine’ use in preterm population.
Research agenda All therapeutic agents should be assessed for meaningful efficacy, as well as long-term safety by a ‘gold standard’-RCT. Five RCTs of similar design to examine the appropriate oxygen saturation levels to guide oxygen therapy in preterm infants are now underway. Whether these trials will be able to answer all the relevant questions, remains to be seen. Postnatal steroid therapy should not be totally discarded; clinicians should seriously consider reexamining this potentially powerful therapy in CLD.
References 1. Weis CM, Cox CA, Fox WW. Oxygen therapy. In: Spitzer AR, editor. Intensive care of the fetus and newborn. St. Louis: Mosby; 1996. p. 538e45. 2. Tin W, Hey E. The medical use of oxygen: a century of research in animals and humans. Neo Reviews 2003;4:e340e9. 3. Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia: a clinical approach. Med J Aust 1951; ii:48e50. 4. Askie LM, Henderson-Smart DJ. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants. Cochrane Database Syst Rev 2000;(2):CD001077. 5. Northway WH, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967;267:357e68. 6. Saugstad OD. Bronchopulmonary dysplasia e oxidative stress and oxidants. Semin Neonatol 2003;8:39e49.
7. The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 2000;105:295e310. 8. Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygensaturation targets and outcomes in extremely preterm infants. N Engl J Med 2003;349:959e67. 9. Flynn JT, Bancalari E, Snyder ES, Goldberg RN, Feuer W, et al. A cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity. N Engl J Med 1992;326:1050e4. 10. Tin W, Milligan DWA, Pennefather PM, Hey E. Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation. Arch Dis Child 2001;84:F106e10. 11. Chow L, Wright KW, Sola S. Can changes in clinical practice decrease the incidence of severe retinopathy in very low birth weight infants? Pediatrics 2003;111:339e45. 12. Anderson CG, Benitz WE, Madan A. Retinopathy of prematurity and pulse oximetry: a national survey of recent practices. J Perinatol 2004;24:164e8. 13. Sun SC. Relation of target SpO2 levels and clinical outcome in ELBW infants on supplemental oxygen. Pediatr Res 2002;51: A350. 14. Bradley S, Anderson K, Tin W, et al. Early oxygen exposure and outcome at 10 years in babies of less than 28 weeks gestation. Pediatr Res 2004;55:A373. 15. Poets C, Arand J, Hummler H, et al. Retinopathy of prematurity: a comparison between two centers aiming for different pulse oximetry saturation levels. Biol Neonate 2003;84:A267. 16. Vijayakumar E, Ward GJ, Bullock CE, Patterson ML. Pulse oximetry in infants <1500 gm birth weight on supplemental oxygen: a national survey. J Perinatol 1997;17:341e5. 17. Tin W, Wariyar U. Giving small babies oxygen: 50 years of uncertainty. Semin Neonatol 2002;7:361e7. 18. Silverman WA. A cautionary tale about supplemental oxygen: the albatross of neonatal medicine. Pediatrics 2004;113: 394e6. 19. Millar D, Schmidt B. Controversies surrounding xanthine therapy. Semin Neonatol 2004;9:239e44. 20. Weinberg BA, Bealer BK. The world of caffeine: the science and culture of the world’s most popular drug. New York/London: Routledge, Taylor and Francis; 2002. 21. Davi MJ, Sankaran K, Simons KJ, Simons FE, Seshia MM, et al. Physiologic changes induced by theophylline in the treatment of apnea in preterm infants. J Pediatr 1978;92:91e5. 22. Von Poblotzki M, Rieger-Fackeldey E, Schulze A. Effects of theophylline on the pattern of spontaneous breathing in preterm infants less than 1000 g of birth weight. Early Hum Dev 2003; 72:47e55. 23. Rigatto H, Desai U, Leahy F, Kalapesi Z, Cates D. The effect of 2% CO2, 100% O2, theophylline and 15% O2 on ‘inspiratory drive’ and ‘effective’ timing in preterm infants. Early Hum Dev 1981; 5:63e70. 24. Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. Cochrane Database Syst Rev 1999;(2):CD000432. 25. Henderson-Smart DJ, Steer P. Doxapram versus methylxanthine for apnea in preterm infants. Cochrane Database Syst Rev 2000;(4):CD000075. 26. Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev 2001; (3):CD000140. 27. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Update of Cochrane Database Syst Rev 2000;(2):CD000139. Cochrane Database Syst Rev 2003;(1):CD000139. 28. Hey E, editor. Neonatal formulary. 4th ed. London: BMJ Books; 2003.
Adjunctive therapies in chronic lung disease 29. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, et al. Caffeine therapy for apnoea of prematurity. N Engl J Med 2006; 354:2112e21. 30. Schmidt B, Roberts RS, Davis P, et al. The International Caffeine for Apnea of Prematurity (CAP) trial: preliminary analysis of outcomes at a corrected age of 18e21 months. E-PAS 2007; 61:5130.1. 31. Halliday HL, Ehrenkranz RA, Doyle LW. Early (<96 hours) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1):CD001146. 32. Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7e14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1): CD001144. 33. Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1): CD001145. 34. Shah SS, Ohlsson A, Halliday HL, et al. Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database Syst Rev 2003;(1):CD002058. 35. Shah SS, Ohlsson A, Halliday HL, Shah VS. Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database Syst Rev 2003;(1):CD002057. 36. American Academy of Pediatrics, Committee on Fetus and Newborn; Canadian Pediatric Society, Fetus and Newborn Committee. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330e8. 37. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB. DART Study Investigators. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomised, controlled trial. Pediatrics 2006;117:75e83. 38. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JBDART Study Investigators. Outcome at 2 years of age of infants from the DART study: a multicenter, international, randomised controlled trial of low-dose dexamethasone. Pediatrics 2007; 119:716e21. 39. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics 2005;115:655e61. 40. Brion LP, Soll RF. Diuretics for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev 2001;(2). 41. Brion LP, Primhak RA. Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev 2000;(4):CD001453. 42. Brion LP, Primhak RA, Yong W. Aerosolized diuretics for preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev 2006;(3). 43. Brion LP, Primhak RA, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease. Update of Cochrane Database Syst Rev 2000;(3):CD001817. Cochrane Database Syst Rev 2002;(1): CD001817. 44. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr 2000;136: 717e26. 45. Kang JL, Park W, Pack IS, Lee HS, Kim MJ, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol 2002;92: 795e801. 46. Ballard PL, Gonzales LW, Godinez RI, Godinez MH, Savani RC, et al. Surfactant composition and function in a primate model of infant chronic lung disease: effect of inhaled nitric oxide. Pediatr Res 2006;59:157e62.
51 47. McCurnin DC, Pierce RA, Chang LY, Gibson LL, OsborneLawrence S, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 2005;288:L450e9. 48. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818e9. 49. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819e20. 50. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006;(4):CD000399. 51. Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev; 2006: CD000509. 52. Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, et al. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999;103:610e8. 53. Clark PL, Ekekezie II, Kaftan HA, et al. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child 2002;86: F41e5. 54. Kinsella JP, Walsh WF, Bose CL, Gerstmann DR, Labella JJ, et al. Inhaled nitric oxide in premature neonates with severe hypoxemic respiratory failure: a randomised controlled trial. Lancet 1999;354:1061e5. 55. Field D, Elbourne D, Truesdale A, Grieve R, Hardy P, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115:926e36. 56. Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005;353:13e22. 57. Schreiber MD, Gin-Mestan K, Marks JD, Huo L, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003;349: 2099e107. 58. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006;355:354e64. 59. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PJ, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006;355:343e53. 60. Stark AR. Inhaled NO for preterm infants e getting to yes? N Engl J Med 2006;355:404e6. 61. Bancalari E. Changes in the pathogenesis and prevention of chronic lung disease of prematurity. Am J Perinatol 2001;18: 1e9. 62. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2002;(3):CD000174. 63. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001;344: 1966e72. 64. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;(1):CD004213. 65. Denjean A, Paris-Llado J, Zupan V, Debillon T, Kieffer F, et al. Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasia: a randomised double-blind study. Eur J Pediatr 1998;157:926e31. 66. Ng GY, da Silva O, Ohlsson A. Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane Database Syst Rev 2001;(3):CD003214.
52 67. Wilkie RA, Bryan MH. Effect of bronchodilators on airway resistance in ventilator-dependent neonates with chronic lung disease. J Pediatr 1987;111:278e82. 68. Brundage KL, Mohsini KG, Froese AB, et al. Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia. Am Rev Respir Dis 1990;142:1137e42. 69. Yuksel B, Greenough A. Ipratropium bromide for symptomatic preterm infants. Eur J Pediatr 1991;150:854e7. 70. Watterburg KL, Murphy S. Failure of cromolyn sodium to reduce the incidence of bronchopulmonary dysplasia. Pediatrics 1993; 91:803e6. 71. Viscardi RM, Hasday JD, Gumpper KF, Taciak V, Campbell AB, et al. Cromolyn sodium prophylaxis inhibits pulmonary proinflammatory cytokines in infants at high risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 1997;156:1523e9. 72. Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, et al. Vitamin A supplementation for extremely-low-birth infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 1999;340:1962e8.
W. Tin, T.E. Wiswell 73. Darlow BA, Graham PJ. Vitamin A supplementation for preventing morbidity and mortality in very low birth weight infants. Cochrane Database Syst Rev 2002;(4):CD00501. 74. Wardle SP, Hughes A, Chen S, Shaw NJ. Randomised controlled trial of vitamin A supplementation in preterm infants to prevent chronic lung disease. Arch Dis Child 2001;84:F9e13. 75. Brion LP, Bell EF, Rughuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2003;(4):CD003665. 76. Rosenfeld W, Evans H, Concepcion L, Jhaveri R, Shaeffer H, et al. Prevention of bronchopulmonary dysplasia by administration of bovine superoxide dismutase in preterm infants with respiratory distress syndrome. J Pediatr 1984;105: 781e5. 77. Davis JM, Rosenfeld WN, Richter SE, Parad MR, Gewolb IH, et al. Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome. Pediatrics 1997;100:24e30.
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Adjunctive therapies in chronic lung disease: Examining the evidence Win Tin a,*, Thomas E. Wiswell b a b
The James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK Centre for Neonatal Care, Florida Hospital Orlando, 2718 North Orange Avenue, Suite B, Orlando, FL 32804, USA
KEYWORDS Adjunctive therapy; Chronic lung disease (CLD); Preterm; Respiratory distress syndrome (RDS)
Summary Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) is one of the most common long-term complications in very premature infants. The incidence of CLD has been increasing over the past two decades in parallel with an improvement in the survival of this population. We have witnessed a revolution in the therapies that are used, either to manage these infants’ respiratory distress syndrome (RDS) with an aim to prevent CLD or to manage the established condition. Several devices and strategies have been developed to provide respiratory support with minimal risk of lung injuries. Multiple adjunctive agents have also been used either to reduce the risk of CLD or to mitigate its course. There is considerable evidence supporting the use of exogenous surfactant, but unfortunately many other therapies currently used for CLD, either preventative or as a treatment, are based on very little or no evidence. The gold standard to assess a given therapy is the randomised controlled trial (RCT), designed to look at clinically meaningful outcomes and long-term safety. In this context, we discuss the support e or lack thereof e for the adjunctive therapies used in relation to CLD. Many of the therapies have been examined as systematic reviews by the Cochrane Neonatal Review Group. These reviews are noted in the references and can be easily accessed at the following website sponsored by the National Institute of Child Health and Human Development: www.nichd.nih.gov/ cochrane/default.cfm. Published by Elsevier Ltd.
Introduction Chronic lung disease (CLD) continues to be one of the most common long-term complications associated with preterm birth. Despite improvement in neonatal respiratory care, the incidence of CLD continues to be high, especially as survival of extremely premature infants has improved.
Although the primary pathology of CLD is related to lungs, it is in fact a multisystem disease and, once established, the treatment remains mostly supportive. In this article, we provide the rationale and scientific evidence for the strength and weaknesses of some of the commonly used therapies, which remains mostly individual- or institutionspecific, and hope that this will help clinicians critically to appraise their own practices.
* Corresponding author. Tel.: þ44 (0)1642 854 834; fax: þ44 (0)1642 854 874. E-mail address: [email protected] (W. Tin). 1744-165X/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.siny.2007.09.008
Adjunctive therapies in chronic lung disease
Oxygen therapy Supplemental oxygen is probably the most commonly used therapy in preterm infants who have RDS and CLD, along with other therapeutic adjuncts. The ultimate goal of oxygen therapy is to achieve adequate tissue oxygenation, but without creating oxygen toxicity and oxidative stress. In addition to the inspired oxygen, tissue oxygenation depends upon several other factors, including gas exchange mechanism within the lungs, oxygen-carrying capacity of the blood (approximately 97% of oxygen transported to the tissue is carried by the haemoglobin and 3% is dissolved in plasma), cardiac output and local tissue oedema or ischaemia.1 Therefore, optimising these factors may allow adequate oxygenation with the use of minimal supplemental oxygen. Oxygen was discovered by Priestley, along with Scheele and Lavoisier, in 1774. The experimental work and research carried out over more than a century have shown that like any other ‘drug’, too much oxygen can be toxic and damaging.2 Oxygen toxicity as an important cause of retinopathy of prematurity (ROP) was first described by Campbell,3 and this observation was confirmed by controlled trials more than 50 years ago.4 Direct exposure to high concentrations of oxygen can damage the pulmonary epithelium, and this has also been recognised as an important cause of bronchopulmonary dysplasia (BPD), ever since BPD was first described by Northway et al.5 Even if the inspired oxygen is not high, oxidative stress (defined as an imbalance between pro- and antioxidant forces) can occur, especially in preterm infants who are more vulnerable to the harmful effects of free oxygen radicals.6 Two RCTs have been conducted to see whether it is better to aim for high oxygen saturation in preterm infants who are more than a few weeks old. The American STOP-ROP trial7 which recruited 649 babies with a mean birth gestation of 25.4 weeks showed that keeping fractional oxygen saturation above 95% slightly reduced the number of infants with pre-threshold retinopathy who went on to develop disease severe enough to require retinal surgery. However, benefit was only seen in those without evidence of ‘plus disease’ (dilated and tortuous vessels in at least two quadrants of the posterior pole) at recruitment. More unexpectedly, targeting higher oxygen saturation significantly increased the number of infants who remained in hospital, in supplemental oxygen, and who were perceived to need diuretic therapy at 50 weeks’ post-menstrual age (PMA). The result of the Australian BOOST trial was published in 2003.8 The aim of this double-blind study was to see whether maintaining higher oxygen saturations versus standard levels among oxygen-dependent preterm infants improved their growth and development. This study recruited 358 babies of less than 30 weeks’ gestation who remained in supplemental oxygen at 32 weeks’ PMA. Trial oximeters were specially modified to keep targeted functional saturation in the range of either 91e94% or 95e98%, while displaying a level (masked) in the range 93e96%. This well-designed study showed no evidence that the growth and developmental outcome of oxygen-dependent preterm infants was improved by keeping their oxygen saturation in the high range. In keeping with the observation in the STOP-ROP trial, the BOOST trial
45 also showed that infants in the higher oxygen saturation range showed greater use of postnatal steroids and diuretics, more readmissions and more pulmonary-related deaths. To date, there is insufficient evidence to suggest the optimal oxygen level to be aimed for in preterm infants who receive oxygen therapy in the early neonatal period. The largest cohort study ever carried out showed a strong association between the prevalence, as well as severity, of ROP and the duration of exposure to a transcutaneous oxygen pressure (TcpO2) of more than 80 mmHg (w10.7 kPa),9 but no similar study has ever been mounted as it became commonplace to use pulse oximetry as non-invasive continuous monitoring to guide the oxygen therapy. Most observational studies published recently have suggested that in comparison with the ‘liberal approach’ of attempting to maintain high oxygen saturation values (measured by pulse oximetry), the ‘restrictive approach’ of accepting lower oxygen saturation values was associated with lower incidences of ROP (including severe ROP requiring surgery) and CLD, without the increased risk of mortality.10e13 The follow-up information available from one of these studies showed that the ‘restrictive approach’ of oxygen therapy did not increase the risk of cerebral palsy10 and, more relevantly, it was not associated with any disadvantages in terms of intellectual skills, academic achievements, adaptive functioning and behaviour.14 In contrast, a retrospective analysis of an observational data by Poets et al., involving 891 babies of <30 weeks’ gestation and admitted to two neonatal units, using different oxygen saturation limits (80e92% versus 92e97%), showed that the incidence of ROP (more than stage 2) was significantly higher in the unit that used a lower alarm limit (13% versus 6%), although no difference was seen in the incidence of ROP that required surgery.15 The lack of knowledge and ongoing uncertainty about the ‘optimal’ oxygenation for newborn infants making the transition to extrauterine life has led to wide variation of policies on oxygen-monitoring and therapy in neonatal nurseries.16,17 Observational studies over the past 50 years have got us nowhere, and the only way to resolve the uncertainties and controversies of oxygen-monitoring and therapy is to conduct well-designed RCTs.18 In response to the growing demand to resolve the uncertainty of oxygen therapy in very premature babies, an international collaborative effort has been mounted since 2003, to conduct large, multicentre, masked RCTs to answer the question: What oxygen saturation level should be aimed for in very premature infants? Infants of under 28 weeks’ gestation are eligible for these studies if they are less than 24 h of age; with an international collaborative effort, it is envisaged that a total of over 5000 babies will be enrolled into the ‘oxygen trials’. All these trials will address the principal research question: Does varying the concentration of inspired oxygen to maintain a ‘low’ oxygen saturation range of 85e89% versus a ‘high’ range of 91e95% in babies of less than 28 weeks’ gestation from the day of birth until they are breathing air or until 36 weeks’ PMA affect the incidence of 1. Death or severe neurosensory disability at a corrected age of 2 years? 2. Retinal surgery for ROP?
46 3. The need for supplemental oxygen therapy or respiratory support at 36 weeks’ PMA? 4. Patent ductus arteriosus (PDA) and necrotising enterocolitis? 5. Poor growth at 36 weeks’ PMA and at 2 years? There has already been a prospective agreement to combine the individual patient data from all the trials in order to increase the ability to detect much smaller differences of the primary outcome. This controlled trialstrategy of prospective meta-analysis is likely to be established for the first time in neonatal medicine from ‘the oxygen trials’. Until the uncertainties and controversies on oxygen therapy and its monitoring are resolved, clinicians should follow the words of wisdom by Julius Comroe in 1945: ‘‘The clinician must bear in mind that oxygen is a drug and must be used in accordance with well-recognised pharmacologic principles; i.e., since it has certain toxic effects and is not completely harmless (as widely believed in clinical circles) it should be given only in the lowest dosage or concentration required by the particular patient.’’
Methylxanthine therapy Methylxanthines act by non-specific inhibition of adenosine receptors A1 and A2. Adenosine is involved in the regulation of sleep and arousal, susceptibility to seizures and analgesia. The extracellular concentrations of adenosine in the brain increase when energy demand is more than the supply. An imbalance between ATP synthesis and breakdown results in conditions such as seizures, hypoxia, ischaemia and hypoglycaemia.19 The role of adenosine as a neuromodulator under physiological and pathophysiological conditions is an area of extensive investigation, which is, as yet, incompletely understood. The methylxanthines, aminophylline, theophylline and caffeine, have been used for more than three decades to treat apnoea of prematurity.20 This widespread use of methylxanthines is based entirely on the reports on the short-term outcomes, and until recently, there was no data on the long-term effects including safety. Theophylline has been observed to reduce apnoea by increasing the sensitivity to carbon dioxide21 and improving the minute ventilation.22 The effect on improvement in tidal volume by methylxanthines has been observed to be similar to other stimulants such as 2% CO2 and 100% O2, with little or no change in respiratory frequency.23 There are limited numbers of studies to evaluate the clinical effects of methylxanthine therapy. The results of the meta-analysis for prevention of apnoea in preterm babies by the prophylactic use of methylxanthines,24 or its comparison with doxapram in preventing apnoea,25 do not show any significant benefit. However, in a meta-analysis of 192 infants from five trials, there was a reduction in recurrent apnoea and use of intermittent partial pressure ventilation in the first 2e7 days of methylxanthine use.26 The 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 with the number needed to treat being 3.7 (2.7, 6.7). However, this
W. Tin, T.E. Wiswell benefit was observed in babies under 1000 g and those less than a week old. The advantages were lost if babies were below 1000 g and over 1 week of age, or 1000e1250 g who had failed extubation once.27 Caffeine (usually in the form of caffeine citrate) is now the preferred choice as routine drug monitoring is not necessary because of its wider margin between the therapeutic and toxic levels.28 Schmidt et al. recently reported the short-term outcome ‘at neonatal discharge’ of 2006 preterm infants with a birthweight between 500 g and 1250 g.29 This multicentre double-blind study, known as the CAP (caffeine for apnoea of prematurity) trial, showed that caffeine reduced the duration of supplemental oxygen therapy, continuous positive airway pressure and mechanical ventilation. Treated infants were less likely to have BPD, defined as a need for supplemental oxygen at 36 weeks’ PMA. Unexpectedly, caffeine therapy was also found to be associated with a reduction in the risk of PDA deemed to need pharmacological and surgical closure. This large study also provides some reassurance that caffeine did not increase the risk of neonatal complications, including necrotising enterocolitis and ultrasonographic evidence of brain injuries. Available data on the long-term follow-up of this study also showed that caffeine therapy for apnoea of prematurity improves the rate of survival without neurodevelopmental disability in very low birthweight infants at a corrected age of 18e21 months.30 The CAP trial is one of the best examples of using a ‘gold standard’ to examine the evidence for use of a therapy commonly used in neonatal medicine.
Corticosteroid therapy Systemic and inhalational corticosteroids have been used to prevent or treat CLD in preterm infants. These therapies have been given early (<96 h of age)31 and moderately early (7e14 days of age)32 with the aim of preventing CLD, or delayed/late (>3 weeks of age)33 as treatment for CLD. Both ‘early’ and ‘moderately early’ systemic corticosteroids significantly reduce the incidence of CLD at either 28 days of age or 36 weeks’ PMA. Moderately early treatment was associated with the reduction in mortality through 28 days of age but not thereafter, and there was no reduction in mortality following early treatment. Unfortunately more adverse effects including hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection were observed following both early and moderately early treatments.31,32 More relevantly, in the trials that have reported long-term follow-up information, significantly higher adverse neurodevelopmental outcomes (developmental delay, cerebral palsy, abnormal neurological examinations) were seen following early systemic corticosteroid therapy.31 There was no evidence of an increase in adverse neurodevelopmental outcomes following moderately early treatment with systemic corticosteroids; however, the follow-up data was limited.32 ‘Delayed/late’ systemic corticosteroids had no effect on mortality and had a borderline effect on reducing the incidence of CLD at 36 weeks’ PMA. There was no increase in the occurrence of infection, hyperglycaemia, or gastrointestinal complications,
Adjunctive therapies in chronic lung disease but hypertension was significantly more common with delayed corticosteroid therapy in preterm infants. Although there was an increased rate of abnormal neurological examination among those receiving delayed corticosteroid therapy, there was no increase in the rates of cerebral palsy and major neurosensory disabilities.33 However, information on this long-term outcome is limited. Two systematic reviews of inhalational versus systemic corticosteroids have shown that there was a borderline increase in CLD at 36 weeks’ PMA following the use of inhaled compared to systemic steroids in preventing CLD,34 and that inhaled corticosteroids are no more effective than systemic corticosteroids as treatment in established CLD.35 There is no long-term outcome data available from studies using inhaled corticosteroids to prevent or treat CLD. In view of the concerns about long-term adverse effect on neurodevelopment and short-term side-effects, the Committee on Fetus and Newborn of the American Academy of Pediatrics and Canadian Pediatric Society recommended against the routine use of corticosteroids to prevent or treat CLD.36 However, a recently published double-blind RCT, which had recruited 70 ventilator-dependent infants of less than 28 weeks’ gestation or less than 1000 g to receive either a low-dose dexamethasone or placebo after the first week of life, found that corticosteroid therapy shortened the duration of intubation, without any shortterm complications,37 and showed no obvious long-term harm in terms of neurosensory outcome, blood pressure or hospital readmissions.38 The study was originally designed to detect 10% difference in the rate of survival without major neurosensory disability with an adequate power. However, it was stopped with less than 10% of the target sample size because of very poor recruitment and, therefore, the effect of low-dose dexamethasone on long-term development cannot be conclusive. A meta-regression analysis of 28 RCTs with available follow-up data from 1721 randomised infants showed that the impact of postnatal corticosteroids on the combined outcome of death or cerebral palsy was also modified by the risk of CLD in the control group of infants (Fig. 1).39 Based on the evidence that adverse effects of postnatal corticosteroids may be related to high dose and its early use on infants with relatively lower risk of CLD, clinicians should seriously consider reexamining this potentially powerful therapeutic agent in CLD.
Diuretic therapy Lung oedema and PDA may complicate RDS in preterm infants. These complications, along with renal insufficiency, are the main reasons that furosemide is the most common diuretic used in the early neonatal period. Furosemide is a rapidly acting diuretic on the loop of Henle, inhibiting active reabsorption of chloride and leading to active reabsorption of sodium. In addition, furosemide also has a direct effect on reabsorption of lung fluid and can improve the lung function for a short period. The half-life of furosemide in term infants is about 8 h, but it may be as long as 24 h in preterm infants. Prolonged use increases renal loss of sodium and potassium and also urinary calcium excretion and the risk of renal calcium deposition.
47
Figure 1 Risk difference (RD) % for death or cerebral palsy (CP) among all participants in 14 randomised controlled trials versus rate of chronic lung disease (CLD) in the control group. Each study is shown by a circle whose area is proportional to that study’s weight. Regression line (solid) and its 95%CI (dotted) showed that with risks for CLD below 35%, postnatal corticosteroid therapy significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance (Reproduced with permission from Doyle LW, et al.39).
Early use of furosemide is associated with increased incidence of PDA in preterm infants as it stimulates the production of prostaglandin E2 from the kidneys. Repeated use of this therapy in preterm infants increases the risk of ototoxicity and it can also enhance the risk of aminoglycoside ototoxicity.28 Bumetanide is another ‘loop’ diuretic with a similar mechanism of action, but it is more potent and probably less ototoxic than furosemide. However, it can also cause significant urinary losses of sodium, chloride and calcium and its neonatal use has not been fully evaluated.28 A systematic review of the use of furosemide for RDS in preterm infants has shown that this therapy had no effect on meaningful outcomes, including duration of mechanical ventilation and oxygen supplementation, length of hospitalisation and more relevantly, on mortality and CLD.40 All the six trials included in this review were carried out before the era of antenatal steroid and surfactant replacement therapy, and there is no current evidence to support the routine use of furosemide or any other diuretics in preterm infants who have RDS. The distal tubule diuretic, thiazide, the potassium-sparing diuretic, spironolactone, and the loop diuretic, furosemide, are commonly used in preterm infants who have established CLD. These diuretics are administered parenterally, enterally, or by inhaled aerosol to reduce alveolar and interstitial lung oedema and to improve pulmonary mechanics. A thiazide diuretic, chlorothiazide, is often used in combination with spironolactone for the control of pulmonary oedema in preterm infants with severe CLD, and this is felt to be the safest diuretic combination for long-term use. Chlorothiazide inhibits reabsorption of sodium and chloride from the urine in distal convoluted tubules, thereby increasing the excretion of sodium and subsequently, potassium. Spironolactone is a potassium-sparing diuretic that inhibits the action of aldosterone on distal tubules. Thiazide
48 diuretic in combination with spironolactone can also cause excessive urinary calcium loss and subsequent bone demineralisation and nephrocalcinosis in preterm infants.28 Despite their widespread use, there are surprisingly few data assessing the meaningful value of diuretic therapy in CLD. All the systematic reviews to assess the risks and benefits of furosemide (including aerosolised form) as well as thiazides (with or without spironolactone) in preterm infants with, or developing, CLD have shown improvements in both oxygenation and lung compliance. However, these studies focused on pathophysiological parameters and the findings cannot be translated to the improvement in meaningful outcomes (mortality, duration of mechanical ventilation and oxygen dependency and length of hospital stay).41e43 Of all the adjunctive therapies used in preterm infants with CLD, diuretic therapy is one of the most abused without evidence of substantive benefit.
Inhaled nitric oxide therapy Nitric oxide is a highly diffusible colourless gas produced by many cells in the body including endothelial-lining cells of the blood vessels. Nitric oxide is a potent vasodilator because of its effect as ‘relaxing factor’ on the vessel tone. Inhaled nitric oxide (iNO) can produce potent selective pulmonary vasodilatation without lowering systemic blood pressure as the gas has a very short half-life (2e4 s) in the body,28 which forms the physiological rationale for the clinical use of iNO in newborn infants with pulmonary hypertension. In infants with predominantly intrapulmonary shunting due to atelectasis and ventilation perfusion mismatch, iNO may also improve oxygenation by redirecting blood from poorly aerated or diseased lung regions to better aerated spaces e the ‘micro selective effect’.44 Animal studies have also suggested that iNO reduces lung inflammation,45 improves surfactant function46 and promotes lung growth.47 The initial reports on the benefit of iNO in infants with persistent pulmonary hypertension and hypoxaemic respiratory failure were published in 1992,48,49 and evidence from RCTs have already shown that iNO therapy improved oxygenation and reduced the risk of death or requirement for treatment with extracorporeal membrane oxygenation (ECMO) in respiratory failure in infants born at, or near term (34 weeks’ gestation).50 However, the role of iNO in preterm infants with hypoxaemic respiratory failure, both in terms of its efficacy and safety is less clear and remains controversial.51 The pilot studies on preterm infants with severe CLD have suggested that iNO therapy was safe and was associated with short-term improvement in oxygenation.52,53 However, to date, there are no other clinical data to support the use of iNO in infants with established, severe CLD. Most RCTs in preterm infants with ‘severe’ respiratory failure have shown that iNO did not reduce the risk of death or CLD. A double-blind RCT by Kinsella et al. looking at the efficacy of low-dose iNO (5 ppm) on 80 preterm infants with severe hypoxaemic respiratory failure did not show any differences in the primary outcome measure of ‘survival to discharge’, though there was an observed short-term improvement in oxygenation among treated infants.54 Another multicentre RCT carried out in the UK and the
W. Tin, T.E. Wiswell Republic of Ireland to evaluate the efficacy of iNO in preterm infants (<34 weeks’ gestation) with severe respiratory failure, showed that there was no evidence of an effect of iNO on the primary outcomes: death or severe disability at 1 year corrected age; death or supplemental oxygen on expected date of delivery; or death or supplemental oxygen at 36 weeks’ PMA. Furthermore, this study also showed that ‘mean total costs’ at 1 year corrected age were significantly higher in a group of infants allocated to receive iNO, partly because of the cost of the gas, but mainly because of the difference in initial hospitalisation costs.55 The main drawback of this study was its poor recruitment of only 108 infants despite the planned sample size of 200 infants. A large multicentre study by Van Meurs et al. also showed that iNO has no impact on the risk of death or CLD in preterm infants with a birthweight of <1500 g and with severe respiratory failure. In fact, this study suggested an increased risk of death with iNO therapy amongst infants with a birthweight of <1000 g.56 However, a single-centre study by Schreiber et al. demonstrated that iNO reduced the risk of death and BPD in preterm infants with RDS. Treated infants also had a reduced risk of brain injuries, as evident on ultrasonography, and more relevantly, had a better neurodevelopmental outcome compared to the control group.57 Nonetheless, it is important to note that the rates of CLD and brain injuries were higher than expected in the control group of infants who received oxygen as a placebo. Two recently reported large RCTs have hinted at the potential benefits of iNO in preterm infants with a birthweight between 500 g and 1250 g. Although the mean gestational age of infants was the same in both studies, the age at which iNO was initiated, the dose of iNO and the duration of intervention were considerably different. In the trial by Kinsella et al. (2006), infants who were receiving mechanical ventilation and who were less than 48 h of age were randomly assigned to receive either 5 ppm of iNO or nitrogen as a placebo. This trial did not show a reduction in the overall incidence of CLD by ‘early’ iNO therapy, with the exception of the pre-stratified group of infants with a birthweight between 1000 g and 1250 g (16% of the study group). However, iNO therapy was found to have reduced the incidence of brain injuries in this trial.58 In contrast, the trial by Ballard et al. enrolled infants who were ventilator-dependent (and also infants with a birthweight between 500 g and 799 g who were on continuous positive airway pressure) at 7e21 days. Treated infants received iNO 20 ppm for 48e 96 h, with a dose reduction at weekly intervals. This large trial showed that iNO improved the survival without CLD at 36 weeks’ PMA but this improvement in the primary outcome was only limited to infants who were 7e14 days of age at randomisation. The complications of prematurity, including ultrasonographic evidence of brain injuries, were not different between the two groups.59 Although these two recent studies have suggested that iNO may be of benefit in preterm infants who were less critically ill, and the findings on brain injuries are reassuring, the most effective dose, timing and duration of iNO therapy and the selection of infants most likely to benefit from this therapy remain uncertain. Because iNO is one of the most expensive therapies and there is a lack of long-term follow-up information, the ‘routine’ use of iNO therapy in preterm infants is not justifiable and should be limited to clinical trials.60
Adjunctive therapies in chronic lung disease
Other adjunctive therapies Indomethacin and ibuprofen therapy
49 chemotaxis, and as such could help to regulate the inflammatory processes in the lung. Two small RCTs have been performed to assess the early use of this therapy in preventing CLD.70,71 Both trials showed no difference in mortality or CLD (at 28 days and 36 weeks’ PMA). There has been no RCT to assess cromolyn therapy for established CLD and so also this therapy cannot be recommended in the management of CLD.
PDA is one of the risk factors for CLD in preterm infants.61 Indomethacin, a cyclo-oxygenase inhibitor, has been the mainstay in treating or preventing PDA over the past 25 years.62 It is reasonable to assume that a treatment regimen that prevents PDA should reduce the risk of CLD in this population. The largest RCT to assess the outcomes following the early prophylactic use of indomethacin in very low birthweight infants (International Trial of Indomethacin Prophylaxis in Preterms [TIPP])63 showed a significant reduction in the incidence of PDA following indomethacin therapy. However, there was no reduction in the incidence of CLD, a finding similar to all other RCTs that have assessed this therapy.62 Ibuprofen, another cyclo-oxygenase inhibitor has been shown to be equally effective in PDA closure. Its use is gaining in popularity over the past decade as it does not cause reduction in regional blood flow to the brain, kidneys and gut.28 It has also been assessed in RCTs, with results similar to those seen with indomethacin e neither a significant reduction nor even a trend towards reduction in CLD was observed.64
Vitamin A is involved in the regulation and promotion of growth and differentiation of multiple cells. It also maintains the integrity of respiratory tract epithelial cells. Very preterm infants are relatively deficient in vitamin A, which has been shown to be associated with CLD. A large RCT of 807 infants with a birthweight of less than 1000 g has shown that a large dose of intramuscular vitamin A, given three times a week for 4 weeks from birth, slightly decreased the risk of CLD (OR 0.89; 95%CI 0.8e0.99).72 Other smaller trials have also pointed to a similar conclusion.73 However, this preventative therapy requires several injections. A trial of oral vitamin A therapy daily for 4 weeks in a similar population of infants failed to detect any benefit.74
Beta-receptor agonist therapy
Vitamin E therapy
Bronchodilators, such as beta-receptor agonists, are potentially attractive therapies for preterm infants with CLD, as bronchial hyperactivity and responsiveness may be found in this population, while assisted ventilation may also aggravate the response. One double-blind RCT using inhaled salbutamol (albuterol) and beclomethasone to prevent CLD found no evidence that this therapy reduced mortality, oxygen dependency at 28 days, duration of ventilation and duration of oxygen supplementation in preterm infants.65 Several studies that assessed the immediate changes in pulmonary mechanics (compliance, resistance) following the use of salbutamol66 have shown variable results, including improvement, no change or even worsening in these respiratory parameters. As so far there has been no RCT to review meaningful clinical outcomes following beta-receptor agonist therapy, the usefulness of beta-receptor agonist therapy in treating infants with CLD remains unknown.
Vitamin E consists of several types of tocopherols with antioxidant activity. As a scavenger of free radicals, it could potentially limit the processes that lead to CLD. Vitamin E has been extensively studied in preterm infants with the expectation that it could help prevent oxidative stress-related damage to multiple organs, but a systematic review of the vitamin E trials in this population indicates that this therapy does not reduce the incidence of CLD.75
It was hoped that the antioxidant superoxide dismutase (SOD) could ameliorate oxygen free radical injury to the premature lungs. However, two small RCTs carried out to assess the effect of SOD in preventing CLD76,77 failed to detect any benefit and the use of SOD in preterm infants cannot therefore be recommended.
Anticholinergic therapy
Conclusions
Ipratropium bromide, a muscarinic antagonist, has some effect on bronchodilation and has been used to treat infants with CLD. The data available are limited to case reports following short-term use of this therapy.67e69 Results are mixed with some reports demonstrating positive effects and some indicating either no or negative effects. Without supportive evidence from an RCT, this therapy cannot be recommended in the management of CLD.
CLD/BPD is still one of the most challenging complications in preterm infants, and carries the potential for mortality and major morbidity. As with much of neonatal care, several therapeutic agents have made their way into the prevention and treatment of this very frustrating condition without being assessed adequately for meaningful efficacy and long-term safety. The careful examination of the evidence for many of these adjunctive therapies shows there is very little or no basis to support the routine use of a vast majority of them. We have a moral obligation to our patients and their families to practice evidence-based medicine and to collaborate with each other in examining the evidence for all therapies commonly used in neonatal medicine.
Cromolyn sodium therapy Cromolyn sodium (disodium cromoglycate) is a mast cell stabiliser that also inhibits neutrophil activation and
Vitamin A therapy
Superoxide dismutase therapy
50
W. Tin, T.E. Wiswell
Practice points Among the therapeutic agents used, either to reduce the risk of chronic lung disease (CLD) or to mitigate its course, several of them are based on very little or no evidence. Caffeine therapy in preterm infants not only reduces the risk of CLD, but also improves the rate of survival without neurodevelopmental disability. Oxygen is probably the most commonly used therapy in preterm infants with respiratory disease syndrome and CLD, but to date there is no good evidence to guide us how much oxygen is appropriate to give to these vulnerable infants. Adverse effects of postnatal steroids may be related to high dose and its early use in infants with relatively low risk of CLD. Two recently published randomised controlled trials (RCTs) suggested that inhaled nitric oxide may be of benefit in preterm infants who were less critically ill, but the evidence available to date does not justify its ‘routine’ use in preterm population.
Research agenda All therapeutic agents should be assessed for meaningful efficacy, as well as long-term safety by a ‘gold standard’-RCT. Five RCTs of similar design to examine the appropriate oxygen saturation levels to guide oxygen therapy in preterm infants are now underway. Whether these trials will be able to answer all the relevant questions, remains to be seen. Postnatal steroid therapy should not be totally discarded; clinicians should seriously consider reexamining this potentially powerful therapy in CLD.
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