The Roles of Drug Therapy Given Via the Endotracheal Tube to Neonates

The roles of drug therapy given via the endotracheal tube to neonates

Anne Greenough1,2, Niovi Papalexopoulou1

1Division of Asthma, Allergy and Lung Biology, MRC & Asthma UK Centre in

Allergic Mechanisms of Asthma, King's College London, London, United Kingdom

2NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation

Trust and King's College London, United Kingdom

Address for correspondence: Professor Anne Greenough, Neonatal Intensive

Care Unit, 4th Floor Golden Jubilee Wing, King’s College Hospital, Denmark Hill,

London, SE5 9RS, United Kingdom. Tel: 0203 299 3037; fax: 0203 299 8284

Email: [email protected]

Key words: neonate, surfactant, pulmonary vasodilators, bronchodilators, diuretics

Word count: 3197

SUMMARY

Many drugs are given to intubated neonates by the inhalation route. The optimum aerosol delivery system, however, has not been identified and there are many challenges in delivering drugs effectively to the lower airways of intubated neonates. The effectiveness of surfactant in prematurely born infants

1 and nitric oxide has been robustly investigated. Other drugs are being used on very limited evidence.

INTRODUCTION

Drug therapy is frequently given to neonates via their endotracheal tube. The majority of drugs are given by aerosolisation, but some are given as a liquid bolus (eg surfactant). The aim of this review is to describe whether the benefits of administering drug therapy via an endotracheal tube have been robustly proven, as well as highlighting the challenges, limitations and indeed potential hazards. In addition, we have included some information on alternative airway delivery routes (see the surfactant section) that is rather than via the endotracheal tube.

Aerosolisation

Aerosol entrainment can be achieved by placing the nebuliser either within the inspiratory arm of the circuit or introducing the aerosol between the patient interface and the “Y” connector. The former position is recommended for metered dose inhalers (MDIs) and vibrating mesh and jet nebulisers, whereas the latter position is recommended for MDIs with a spacer device.[1] Aerosol delivery to the lower airways is small, between one and ten percent in intubated neonates.[2] This is due to their high respiratory rate, low tidal volumes and small airway diameters [3, 4] (Table 1). A further influencing factor is the mode of ventilation, delivery can be affected by the inspiratory time and inspiratory flow pattern. Increasing nebuliser air flow leads to increased aerosol impaction

2 in the upper airways with concomitant decreased deposition in the lungs.

Synchronisation of nebuliser aeration with the patient’s inspiratory efforts reduces the amount of drug lost in expiration, achieving this in neonates, however, is challenging because of their rapid respiratory rate and short inspiratory time. Aerosol particle size is also important, small particles with short inflation times and low inspiratory flows can result in significant exhalation losses. The particles, however, need to be small enough to bypass the interface without much impaction. Aerosolised drugs, if exhaled by the patient, can contaminate the positive end expiratory pressure (PEEP) valve increasing resistance. There are relatively few studies of deposition in neonates, as radio- labelled drugs cannot be used.[5] Much more evidence is required to determine the optimum aerosol delivery system.

Oxygen

Supplementary oxygen is the most frequently used therapy delivered by the endotracheal tube. High concentrations, however, can cause toxicity, resulting in inflammation and fibrosis.[6, 7]. The most appropriate target oxygen saturation levels have been an area of uncertainty and hence investigated in a number of RCTs. An RCT which included 358 infants born at less than 30 weeks of gestational age demonstrated no significant differences in growth, neurodevelopmental abnormalities at 12 months or mortality between those randomised to 91-94% or 95-98% oxygen saturation targets.[8] The high saturation target group predictably required longer hospitalisation and more required supplementary oxygen at 36 weeks PMA and/or home supplementary oxygen.[8]. Meta-analysis of five RCTs demonstrated lower oxygen saturation targets reduced the incidence and severity of retinopathy of prematurity (ROP)

3 without increasing mortality.[9] Subsequenty, RCTs and a meta-analysis which included 4,911 infants of less than 28 weeks of gestational age who were randomised on the first day after birth to 85-89% or 91-95% oxygen saturation target levels was reported.[10] The infants in the low saturation group had a higher mortality and occurrence of necrotising enterocolitis (NEC).[10] Thus, most recommend oxygen saturations of between 91 and 95% in the acute phase of the respiratory illness.

Surfactant

Surfactant replacement therapy is an important part of standard care for prematurely born infants, its efficacy has been robustly demonstrated in multicentre, randomised controlled trials (RCTs) and meta-analyses.[11-13]

Recent guidelines [14, 15] recommend early, selective natural surfactant for prematurely born infants.

Recent studies have investigated the optimum method of administering surfactant in an era of increasing use of non-invasive ventilation. In a recently reported meta-analysis [16], seven ventilation strategies were compared – nasal continuous positive airway pressure (nCPAP) alone, intubation and surfactant administration followed by immediate extubation (INSURE), nebulised surfactant, less invasive surfactant administration (LISA), surfactant administered via laryngeal mask airway, non-invasive intermittent positive pressure ventilation and mechanical ventilation. During LISA, while infants are receiving nCPAP surfactant is given via a thin diameter tube such as a feeding catheter. The tube is directly placed into the trachea using a laryngoscope with or without Magill forceps. The meta-analysis demonstrated compared with

4 mechanical ventilation, LISA was associated with lower odds of the composite outcome of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age

(PMA) or death (odds ratio (OR) 0.49, 95% confidence intervals (CI) 0.30-0.79).

[16] In addition, LISA also had lower odds of BPD or severe intraventricular haemorrhage (IVH). Compared to nasal CPAP (nCPAP), LISA also had a lower odds of BPD or death (OR 0.58, 95% CI 0.35-0.93) and airleak.[16]

Pulmonary Vasodilators

Inhaled Nitric Oxide

Inhaled nitric oxide (iNO) reduces the combined outcome of need for extracorporeal membrane oxygenation (ECMO) or death (relative risk (RR) 0.65,

95% CI 0.54-0.75) in infants born at or near term. This was as a result of the reduction in ECMO requirement.[17] Oxygenation improved in approximately

50% of infants.[17] In prematurely born infants, a systematic review of 14

RCTs put the trials into three groups: entry in the first three days based on oxygenation criteria, routine use in prematurely born infants with pulmonary disease and late enrolment based on an increased risk of BPD. Neither the nine trials of early rescue treatment based on oxygenation criteria or the three studies of routine use in infants with pulmonary disease demonstrated significant reductions in BPD or mortality. Later treatment in infants at risk of BPD (two trials) was not associated with a significant reduction in BPD.[18] An individual patient data meta-analysis which included results from 3298 infants did not find a significant improvement in mortality or BPD.[19] It is possible that the use of higher doses (>5ppm) might be associated with improved outcomes, but this needs further investigation.[19] Current recommendations [20] are that iNO

5 should not be used in prematurely born infants to prevent BPD, but can be beneficial for those with severe hypoxaemia that is, primarily due to persistent pulmonary hypertension of the newborn (PPHN) rather than parenchymal lung disease, particularly if it is associated with prolonged rupture of membranes and oligohydramnios.

Prostacycline

Prostacycline (prostaglandin PGI2) relaxes vascular smooth muscle by activating adenylate cyclase and increasing cyclic adenosine monophosphate.[21] The usefulness of prostacycline administration as epoprostanol is limited by its short half life, but the synthetic analogues iloprost and treprostinil have longer half lives.[21] There are case reports of iloprost use in neonates. In retrospective reviews, iloprost administration has been associated with a reduction in the oxygenation index [22, 23], but in one series five of the 13 infants experienced hypotension requiring treatment with vasopressors or fluids.[23] In another retrospective review, iloprost (n=20) compared to oral sildenafil (n=27) was associated with significantly greater improvements in the time to achieve an adequate clinical response (OI<20, oxygen saturation >90% and

PaO2>60mmHg, p<0.03), the duration of mechanical ventilation (p<0.001) and inotropic support.[24] The study, however, was a retrospective comparative study and the efficacy of inhaled iloprost needs testing in an appropriately designed RCT.

Corticosteroids

6 Systemically administered corticosteroids reduce BPD and facilitate extubation, but have numerous side-effects. Administering corticosteroids by the inhaled route and reducing the systemic side-effects is then an attractive option. Meta- analysis of three trials which compared the efficacy of inhaled to systemic corticosteroids in ventilator dependent infants with a birth weight < 1500 grams or gestational age < 32 weeks and a postnatal age greater than two weeks demonstrated no significant difference in effectiveness, that is reduction in BPD or side-effects.[25] The authors concluded that neither inhaled or systemic steroids should be recommended as standard therapy for ventilated, prematurely born infants. A meta-analysis of eight trials including in total 232 infants evaluated the efficacy of inhaled steroid administration after the first week from birth in preterm infants at high risk of developing BPD. It demonstrated inhaled steroids did not reduce the separate or combined outcomes of death or BPD. Furthermore, inhaled corticosteroids did not impact on failure to extubate or the total duration of mechanical ventilation or oxygen dependency.[26]

The Neonatal European Study of Inhaled Steroids (NEUROSIS) trial examined the effects of inhaled budesonide administered in the first 24 hours after birth versus placebo in 863 infants born at 23 to 27 weeks gestation who required any form of positive-pressure support.[27] They received the intervention until they no longer required supplementary oxygen or positive pressure support or reached a PMA of 32 weeks. A significant reduction in the rate of BPD (RR 0.74,

95% CI 0.60-0.92) was demonstrated in the intervention group.[27] In addition, significant reductions in infants requiring surgical closure of a patent ductus arteriosus (PDA) or reintubation also were noted in the intervention

7 group. Unfortunately, there was a trend towards increased mortality (16.9% versus 13.6%).[27] It was suggested that the increased mortality in the budesonide group could be due to chance or a higher incidence of pneumonia.

[28] The reported rates of sepsis or infection, however, did not differ between the groups in the RCT.[27]

A promising intervention is delivering in-tracheal instillation of budesonide using surfactant as a vehicle. A pilot study of 116 very low birth weight infants

(VLBW) who had severe radiographic respiratory distress syndrome requiring mechanical ventilation and an inspired oxygen concentration of at least 60% was performed. They were randomised to budesonide suspension with surfactant or surfactant alone.[29] The proportion of infants who survived without BPD was significantly higher in the treatment group and no clinically significant adverse effects were reported.[29] Follow up of the participants when they were between two to three years of age demonstrated no significant differences in the physical growth or the results of neurological examination; no sample size calculation, however, was given.[30] A multicentre RCT was then performed by the same group and included 265 infants with severe RDS. The sample size was calculated to detect a difference in the BPD rate of 60% in the control group and

40% in the intervention arm. The intervention group had a lower incidence of

BPD or death (RR 0.58, 95% CI 0.44-0.77), the number needed to treat was

4.1.[31] The incidence of BPD or death in the control arm, however, was 66% and it would be interesting to determine if similar results were obtained in units with a higher rate of survival without BPD. Small RCTs of infants with meconium aspiration syndrome have suggested that inhaled corticosteroids may be

8 beneficial [32-34], but this too needs testing in RCTs appropriately powered to assess clinically meaningful results.

Clara cell 10-kD protein

Non-ciliated, bronchial lung Clara cells produce Clara cell 1b-kD protein (CC10), a small anti-inflammatory protein which is deficient in prematurely born infants.

[35] In a small RCT of 22 infants, the efficacy of one dose of intra-tracheal recombinant human (rh) CC10 at a low (1mg/kg) or a high dose (5mg/kg) following surfactant administration were compared to placebo.[36] A significant decrease in neutrophils and a tendency towards reduced interleukin-6 levels were noted in the rhCC10 groups.[36] The higher compared to the lower dose was associated with a significant increase in days of mechanical ventilation.[37]

Currently there is insufficient evidence to determine the role of rhCC10 in clinical practice.[37]

Pentoxifylline

Pentoxifylline is a xanthine derivative that has been shown to reduce circulating levels of TNF-α and cytokines in neonates. A RCT including 100 infants was performed to determine if nebulised pentoxifylline versus placebo reduced BPD.

No significant effect on BPD at 36 weeks PMA or death prior to 36 weeks PMA was demonstrated.[38]

Superoxide dismutase

Superoxide dismutase is an endogenous anti-oxidant enzyme. Administration of recombinant human CuZnSOD was investigated in a RCT of 202 preterm infants.

There were no significant differences in mortality or the incidence of BPD, but at

9 a median of one year of follow-up in those born less than 27 weeks of gestation, significantly fewer of the treated group had emergency department visits and subsequent hospitalisation.[39] Overall, more of the placebo group had repeated episodes of wheeze or other respiratory illnesses severe enough to require anti-asthma medications.[39] Surprisingly, these promising results have not led to further studies assessing this treatment.

Bronchodilators

A Cochrane review identified only one prospective RCT which fulfilled the inclusion criteria that clinical outcomes should be reported.[40] One study included 173 infants of gestational age less than 31 weeks who required mechanical ventilation on the tenth day and were randomised to receive inhaled salbutamol, beclomethasone and salbutamol, beclomethasone, or placebo for 28 days.[41] Salbutamol, beclamethasone or a combination of the two therapies compared to placebo did not lead to a significant reduction in mortality, the incidence of BPD or the durations of assisted ventilation or oxygen supplementation.[41] In another study, as the administration of salbutamol, a

β-agonist could increase lung fluid absorption, the hypothesis was tested that salbutamol administration would decrease the failure rate of the INSURE technique. Although no significant differences were found in the INSURE failure rate or the duration of nCPAP, the duration of hospitalisation was shorter in the salbutamol group.[42] A retrospective cohort study of infants less than 29 weeks of gestation from the Paediatric Health Information System database identified

33% of 1429 infants with BPD received bronchodilators. Longer duration of mechanical ventilation increased the odds of receiving a bronchodilator (OR

19.6, 11 to 34.6) at > 5 days. There was, however, marked between hospital

10 variation in use.[43] On current evidence, inhaled bronchodilators should be restricted to neonates with wheeze that is compromising their gas exchange and only continued when shown to be associated with clinically important benefits.

Diuretics

Frusemide has been used in an aerolised form in ventilated neonates with BPD or at high risk of developing BPD, it has the potential to increase lung fluid reabsorption and reduce bronchoconstriction. Meta-analysis of eight RCTs investigating the efficacy of inhaled frusemide, however, highlighted there was insufficient evidence of efficacy in those less than three weeks of age. In those older than three weeks of age, a single aerosolised dose of 1 mg/kg transiently improved pulmonary mechanics, but again there was insufficient information regarding a positive effect on clinical outcomes. On current data, inhaled frusemide at either ages cannot be recommended.

Colistin

Ventilator-associated pneumonia (VAP) is an important problem in intubated neonates. Colistin disrupts the outer membrane of bacteria leading to cell death. It was used in the 1960s, but caused neurotoxicity and nephrotoxicity.

There have now been reports of aerosolised colistin, as an adjunctive therapy or monotherapy in term or prematurely born infants with VAP, leading to eradication of bacteria from sputum. None of the adverse effects of systemic colistin were highlighted, but the reports were of cases or small series.[44,45]

Randomised controlled trials are required to confirm or otherwise these preliminary results.

11 Mucolytics

Case series have examined the role of mucolytic drugs in refractory cases of atelectasis [46, 47] coming to different conclusions as to whether recombinant human DNase (rhDNASE) or hypertonic saline is better or perhaps the combination might be more efficacious. In a randomised, placebo, crossover trial of intra-tracheal N-acetylcysteine, two of the ten premature infants with BPD had increased airway resistance and frequency of cyanotic spells and bradycardia when given N-acetylcysteine.[48] The current data do no support use of mucolytic agents in intubated infants.

Heliox

Heliox, a mixture of the inert gas helium and oxygen, has a low density which reduces air flow resistance. In a pilot study of 15 infants with severe BPD, heliox administration for sixty minutes resulted in a significant increase in tidal volume and compliance and a significant decrease in their OI.[49] In another study, heliox administration in ten infants who were studied before extubation was associated with a reduction in their work of breathing.[50] A pilot study of eight ventilated neonates with MAS demonstrated that mechanical ventilation

when heliox was administered was associated with a significant lower FiO2 and alveolar-arterial oxygen tension difference.[51] Randomised trials are required to more robustly determine the efficacy of this therapy.

Use of the anaesthetic gas xenon during therapeutic hypothermia in infants with hypoxic ischaemic encephalopathy (HIE) had been shown in preclinical trials to improve neuroprotection. In a clinical feasibility trial, cooled newborns who were 12 less than 18 hours of age were entered into a single arm, escalation study if they required less than 35% oxygen. Xenon duration was increased stepwise from three to 18 hours in 14 subjects. No adverse respiratory or cardiovascular effects were reported.[52] Seven of eleven survivors had mental and physical developmental scores > 70 at follow up. The total body hypothermia plus Xenon

(TOBY-Xe) trial randomised 92 infants with moderate to severe HIE to cooling alone or cooling in combination with 30% xenon.[53] Magnetic resonance assessments highlighted that xenon did not have additional neuroprotective effects compared with induction of hypothermia alone after birth asphyxia. Two adverse events occurred in desaturation the xenon group, transient and subcutaneous fat necrosis during the MRI.[53] Whether a higher level of xenon

(50%) may be additive is currently being investigated.[54]

Mesenchymal stem cells

There are promising early results of stem cells impacting on BPD development in animal models. Hyperoxia induced BPD in neonatal rats was associated with decreased circulating and resident mesenchymal stem cells (MSC).[55]

Administration of bone marrow derived MSCs or multipotent stromal cells prevented the compromised alveolar and vascular development.[55] In a rat model, hyperoxia exposure led to air space enlargement, loss of lung capillaries and low expression of VEGF and eNOS. Transplanted endothelial progenitor cells, when combined with inhaled nitric oxide (iNO), resulted in improved alveolarisation, microvessel density and upregulation of VEGF and eNOS proteins.[56] Bronchioalveolar stem cells (BASCs) are an adult lung stem cell population capable of self-renewal and differentiation in culture.[57] Treatment of neonatal hyperoxia-exposed mice with MSC and MSC conditional media

13 resulted in an increase in BACs, which may then play a role in lung injury repair in BPD.[57] A phase 1 dose escalation trial has been undertaken to assess the safety and feasibility of a single, intratracheal transplantation of human umbilical cord blood (hUCB) derived MSCs in preterm infants at high risk of BPD.[58]

Nine infants with a mean gestational age of 25.3 weeks were included in the trial. Compared to historical controls, BPD severity was lower in the transplant recipients.[58] MSCs pose a theoretical risk of promoting tumour growth and malignant changes, thus long term follow up is required. In a follow up study of up to sixty months post MSC transplantation of 1012 adult and paediatric patients with mixed pathologies, however, there was no increased incidence of death, malignancy, infection or toxicity.[59] The promising results in neonates requires further investigation in appropriately designed trials with long term follow up.

Conclusions

Effective delivery of aerosolised drugs is challenging in intubated neonates, particularly due to their low tidal volume, rapid respiratory rate and small diameter airways. More work is required to identify the optimum aerosol delivery system. New methods of administering surfactant are being explored as increasingly non invasive ventilation methods are being used, LISA is a promising technique. Inhaled NO remains the pulmonary vasodilator of choice, but iloprost is being used in centres who cannot afford either iNO or ECMO. The delivery of budesonide with surfactant has yielded encouraging results, but more evidence is required before this combination can be recommended. Data currently available do not support use of mucolytics, inhaled diuretics or xenon.

Appropriately designed and powered RCTs are required to assess the efficacy

14 and hazards of the majority of inhaled drugs currently being given to intubated neonates (Table 2).

ACKNOWLEDGEMENTS

Competing interests: None declared

Contributor statement: Both authors undertook the literature review, prepared the manuscript and approved the final version.

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article to be published in Archives of Disease in

Childhood editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence “http://adc.bmjjournals.com/ifora/licence.dtl”.

15 REFERENCES

1. Mazela J, Polin RA. Aerosol delivery to ventilated newborn infants: historical challenges and new directions. Eur J Pediatr 2011;170:433-44.

2. Longest PW, Tian G. Development of a new technique for the efficient delivery of aerosolized medications to infants on mechanical ventilation. Pharm Res 2015;32:321-

3. Cole CH. Special problems in aerosol delivery: neonatal and paediatric considerations. Respir Care 2000;45:646-51.

4. Fok TF, Monkman S, Dolovich M, et al. Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia. Pediatr Pulmonol 1996;21:301-9.

5. Everard ML. Ethical aspects of using readiolabelling in aerosol research. Arch Dis

Child 2003;88:659-61.

6. Jobe AH, Kallapur SG. Long term consequences of oxygen therapy in the neonatal period. Sem Fetal Neonatal Med 2010;15:230-5.

7. Delemos RA, Coalson JJ, Gerstmann DR, et al. Oxygen toxicity in the premature baboon with hyaline membrane disease. Am Rev Resp Dis 1987;136:677-82.

8. Askie LM, Henderson-Smart DJ, Irwig L, et al. Oxygen saturation targets and outcomes in extremely preterm infants. New Engl J Med 2003;349:959-67.

9. Askie LM, Henderson-Smart DJ, Ko H. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants. Cochrane

Database Syst Rev 2009;1:CD001077.

10. Saugstad OD, Aune D. Optimal oxygenation of extremely low birth weight infants: a meta-analsysi and systematic review of the oxygen saturation target studies.

Neonatology 2014;105:55-63.

16 11. Rojas-Reyes M, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev

2012;3:CD000510.

12. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev

2012;11:CD001456.

13. Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2009;2:CD007836.

14. Polin RA, Carlo WA, Papile LA, et al. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics 2014;133:156-63.

15. Sweet DG, Carniell I V, Greisen G, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants -2013 update.

Neonatology 2013;103:353-68.

16. Isayama T, Iwami H, McDonald S, et al. Association of noninvasive ventilation strategies with mortality and bronchopulmonary dysplasia among preterm infants: A systematic review and meta-analysis. JAMA 2016;316:611-24.

17. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006;4:CD000399.

18. Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2010;12:CD000509.

19 Askie LM, Ballard RA, Cutter GR, et al. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics 2011;128:729-39.

20. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the Use of

Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary

Hypertension. J Pediatr 2016;170:312-4.

21. Cosa N, Costa E. Inhaled pulmonary vasodilators for persistent pulmonary hypertension of the newborn: safety issues relating to drug administration and delivery devices. Med Devices (Auckl). 2016;9:45-51.

17 22. Yilmaz O, Kahveci H, Zeybek C, et al. Inhaled iloprost in preterm infants with severe respiratory distress syndrome and pulmonary hypertension. Am J Perinatol

2014;31:321-6.

23. Brown AT, Gillespie JV, Miquel-Verges F, et al. Inhaled epoprostenol therapy for pulmonary hypertension: Improves oxygenation index more consistently in neonates than in older children. Pulm Circ 2012;2:61-6.

24. Kahveci H, Yilmaz O, Avsar UZ, et al. Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn. Pediatr Pulmonol 2014;49:1205-

25. Shah SS, Ohlsson A, Halliday HL, et al. Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database Syst Rev 2012;5:CD002057.

26. Onland W, Offringa M, van Kaam A. Late (≥ 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev

2012;4:CD002311.

27. Bassler D, Plavka R, Shinwell ES, et al. Early inhaled budesonide for the prevention of bronchopulmonary dysplasia. New Engl J Med 2015;373:1497-506.

28. Schmidt B. No End to Uncertainty about Inhaled Glucocorticoids in Preterm

Infants. New Engl J Med 2015;373:1566-7.

29. Yeh TF, Lin HC, Chang CH,et al. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics 2008;121:e1310-8.

30. Kuo HT, Lin HC, Tsai CH, et al. A follow-up study of preterm infants given budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants. J Pediatr 2010;156:537-41.

31. Yeh TF, Chen CM, Wu SY, et al. Intratracheal Administration of

Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care

Med 2016;193:86-95.

18 32. Tripathi S, Saili A. The effect of steroids on the clinical course and outcome of neonates with meconium aspiration syndrome. J Trop Pediatr 2007;53:8-12.

33. Basu S, Kumar A, Bhatia BD, et al. Role of steroids on the clinical course and outcome of meconium aspiration syndrome-a randomized controlled trial. J Trop Pediatr

2007;53:331-7.

34. Garg N, Choudhary M, Sharma D, et al. The role of early inhaled budesonide therapy in meconium aspiration in term newborns: a randomized control study. J

Maternal Fetal Neonatal Med 2016;29:36-40.

35. Loughran-Fowlds A, Oei J, Wang H, et al. The influence of gestation and mechanical ventilation on serum clara cell secretory protein (CC10) concentrations in ventilated and nonventilated newborn infants. Pediatr Res 2006;60:103-8.

36. Levine CR, Gewolb IH, Allen K, et al. The safety, pharmacokinetics, and anti- inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res 2005;58:15-21.

37. Abdel-Latif ME, Osborn DA. Intratracheal Clara cell secretory protein (CCSP) administration in preterm infants with or at risk of respiratory distress syndrome.

Cochrane Database Syst Rev 2011;5:CD008308.

38. Lauterbach R, Szymura-Oleksiak J, Pawlik D, et al. Nebulized pentoxifylline for prevention of bronchopulmonary dysplasia in very low birth weight infants: a pilot clinical study. J Maternal Fetal Neonatal Med 2006;19:433-8.

39. Davis JM, Parad RB, Michele T, et al. Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics 2003;111:469-76.

40. Ng GY, Da S, Ohlsson A. Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane Database Syst Rev 2001;3:CD003214.

41. Denjean A, Paris-Llado J, Zupan V, et al. Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasia: a randomised double-blind study. Eur J

Pediatr 1998;157:926-31.

19 42. Dehdashtian M, Malakian A, Aramesh MR, et al. Effectiveness of intratracheal salbutamol in addition to surfactant on the clinical course of newborns with respiratory distress syndrome: a clinical trial. Ital J Pediatr 2016;42:6.

43. Slaughter JL, Stenger JR, Reagan PB, et al. Inhaled bronchodilator use for infants with bronchopulmonary dysplasia. J Perinatol 2015;35:61-6.

44. Kang CH, Tsai CM, Wu TH, et al. Colistin inhalation monotherapy for ventilator- associated pneumonia of Acinetobacter baumannii in prematurity. Pediatr Pulmonol

2014;49:381-8.

45. Nakwan N, Wannaro J, Thongmak T, et al. Safety in treatment of ventilator- associated pneumonia due to extensive drug-resistant Acinetobacter baumannii with aerosolized colistin in neonates: a preliminary report. Pediatr Pulmonol 2011;46:60-6.

46. Dilmen U, Karagol BS, Oguz SS. Nebulized hypertonic saline and recombinant human DNase in the treatment of pulmonary atelectasis in newborns. Pediatr Int

2011;53:328-31.

47. Altunhan H, Annagur A, Pekcan S, et al. Comparing the efficacy of nebulizer recombinant human DNase and hypertonic saline as monotherapy and combined treatment in the treatment of persistent atelectasis in mechanically ventilated newborns.

Pediatr Int 2012;54:131-6.

48. Bibi H, Seifert B, Oullette M, et al. Intratracheal N-acetylcysteine use in infants with chronic lung disease. Acta Paediatr 1992;81:335-9.

49. Szczapa T, Gadzinowski J, Moczko J, et al. Heliox for mechanically ventilated newborns with bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed

2014;99:F128-33.

50. Migliori C, Gancia P, Garzoli E, et al. The Effects of helium/oxygen mixture

(heliox) before and after extubation in long-term mechanically ventilated very low birth weight infants. Pediatrics 2009;123:1524-8.

51. Szczapa T, Gadzinowski J. Use of heliox in the management of neonates with meconium aspiration syndrome. Neonatology 2011;100:265-70.

20 52. Dingley J, Tooley J, Liu X, et al. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics 2014;133:809-18.

53. Azzopardi D, Robertson NJ, Bainbridge A, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia

(TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet Neurol

2015 [Epub ahead of print].

54. ClinicalTrials.gov. Xenon and Cooling Therapy in Babies at High Risk of Brain

Injury Following Poor Condition at Birth (CoolXenon3). 2015.

55. van Haaften T, Byrne R, Bonnet S, et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injuary in rats. Am J Respir Crit

Care Med 2009;180:1131-42.

56. Lu A, Sun B, Qian L. Combined iNO and endothelial progenitor cells improve lung alveolar and vascular structure in neonatal rats exposed to prolonged hyperoxia. Pediatr

Res 2015;77:784-92.

57. Tropea KA, Leder E, Aslam M, et al. Bronchialveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia.

Am J Physiol Lung Cell Mol Physiol 2012;302:L829-37.

58. Chang YS, Ahn Sy, Yoo HS, et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr 2014;164:944-72.

59. Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS

One 2012;7:e47559.

21 Table 1: Factors affecting drug delivery by aerosolisation

 Particle size

 Respiratory rate

 Tidal volume

 Airway diameter

 Inspiratory flow

 Inspiratory time

 Synchronisation of actuation

22 Table 2: Efficacious inhaled drugs in intubated neonates

Proven Unproven More evidence is required Surfactant Diuretics Corticosteroids (inhaled) Nitric oxide Bronchodilators Prostacycline Mucolytics Budesonide with surfactant rhCC10 Pentoxyfilline Colistin Heliox Superoxide dismutase Xenon