oulu 2018 d 1480 university of oulu p.o. box 8000 fi...
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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-2024-6 (Paperback)ISBN 978-952-62-2025-3 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1480
AC
TAP
ia Härkin
OULU 2018
D 1480
Pia Härkin
CLOSURE OF PATENT DUCTUS ARTERIOSUS IN VERY PRETERM INFANTSPOTENTIAL ROLE OF PARACETAMOL AND CONSEQUENCES OF CURRENT TREATMENTS
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE:MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
ACTA UNIVERS ITAT I S OULUENS I SD M e d i c a 1 4 8 0
PIA HÄRKIN
CLOSURE OF PATENT DUCTUS ARTERIOSUS IN VERY PRETERM INFANTSPotential role of paracetamol and consequences of current treatments
Academic dissertation to be presented with the assent ofthe Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium 12 of Oulu University Hospital, on 16November 2018, at 12 noon
UNIVERSITY OF OULU, OULU 2018
Copyright © 2018Acta Univ. Oul. D 1480, 2018
Supervised byProfessor Mikko HallmanDocent Timo Saarela
Reviewed byDocent Tiina OjalaDoctor Viena Tommiska
ISBN 978-952-62-2024-6 (Paperback)ISBN 978-952-62-2025-3 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2018
OpponentDocent Hanna Soukka
Härkin, Pia, Closure of patent ductus arteriosus in very preterm infants. Potentialrole of paracetamol and consequences of current treatmentsUniversity of Oulu Graduate School; University of Oulu, Faculty of Medicine, MedicalResearch Center Oulu; Oulu University HospitalActa Univ. Oul. D 1480, 2018University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
The ductus arteriosus connects the pulmonary artery and the descending aorta in the foetus. Innormal neonatal transition, the ductus closes soon after birth. If the duct remains significantly openafter birth, it may complicate the recovery of a very preterm infant. Present treatments of patentductus arteriosus (PDA) are either medical (ibuprofen or indomethacin) or surgical (ligation).However, these treatments can have serious side effects, especially in the most immature infants.This doctoral thesis studied the potential role of intravenous paracetamol for PDA treatment invery preterm infants born before 32 weeks of gestation. Consequences of the PDA treatments inan epidemiological birth cohort were also studied. In retrospective Study I stated that treatmentsof PDA decreased after the introduction of IV paracetamol for early pain management in preterminfants. Study II showed in a randomised clinical trial for the first time that paracetamol has abiological effect on the ductus arteriosus in preterm infants soon after birth. The ductus closedsignificantly earlier in the paracetamol group than in the placebo group. The epidemiologicalcohort Study III showed evidence that both medical and surgical treatment of PDA associated withsevere bronchopulmonary dysplasia in infants born very preterm. Additionally, surgical PDAligation was associated with increased risk of necrotising enterocolitis and intraventricularhaemorrhage. Study IV showed that treatment of PDA was not associated with increasedmortality, even in the most immature preterm infants born before 28 weeks of gestation.
Keywords: cohort study, morbidity, paracetamol, patent ductus arteriosus, PDAepidemiology, PDA treatment, very low gestational age infant
Härkin, Pia, Hyvin pienen keskosen avoimen valtimotiehyen sulku. Parasetamoli-hoidon merkitys ja nykyhoitojen sivuvaikutuksetOulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical ResearchCenter Oulu; Oulun yliopistollinen sairaalaActa Univ. Oul. D 1480, 2018Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Valtimotiehyt on sikiöaikana avoimena oleva suoni, joka yhdistää keuhkovaltimon laskevaanaorttaan ja ohjaa vähähappisen veren istukkaan. Yhdessä soikean aukon kanssa suoni takaa siki-ön verenkierron normaalin toiminnan ennen keuhkojen avautumista. Mikäli valtimotiehyt jääsyntymän jälkeen pitkittyneesti auki, muuttaa se keskosen verenkiertoa siten, että osa aortanverenkiertoa ohjautuu keuhkoverenkiertoon vaikeuttaen pienen keskosen toipumista. Nykyhoi-toina käytetään joko lääkkeellistä (ibuprofeeni tai indometasiini) tai kirurgista sulkua. Lääkkeel-linen hoito ei ole kovin tehokas kaikista epäkypsimmillä keskosilla ja hoitoihin liittyy vakavia-kin sivuvaikutuksia.
Väitöskirjassa tutkittiin parasetamolilääkityksen vaikutusta hyvin pienen keskosen avoimenvaltimotiehyen sulkeutumiseen. Epidemiologisessa osiossa tutkittiin nykyhoitojen sivuvaikutuk-sia hyvin pienillä keskosilla. Osatyössä I todettiin, että avoimen valtimotiehyen hoidon tarveväheni merkittävästi sen jälkeen kun parasetamoli oli otettu käyttöön kivun hoidossa vastasynty-neiden teholla. Osatyö II oli satunnaistettu ja sokkoutettu hoitotutkimus, jossa todettiin alkupe-räishavaintona, että parasetamolilla on biologinen vaikutus keskosen avoimeen valtimotiehyeen.Parasetamolia saaneilla keskosilla valtimotiehyt sulkeutui aikaisemmin kuin verrokeilla. Hoidol-la ei todettu merkittäviä sivuvaikutuksia. Osatöissä III ja IV tutkittiin kaikkien vuosina2005−2013 Suomessa syntyneiden hyvin pienten keskosten avoimen valtimotiehyen hoitoja.Lääkehoidolla (ibuprofeeni ja indometasiini) ja kirurgisella hoidolla todettiin olevan yhteys kes-kosen kroonisen keuhkotaudin (BPD) vaikeimpaan muotoon. Kirurgisella hoidolla oli yhteyskeskosen vaikeaan suolitulehdukseen ja vaikeaan aivoverenvuotoon. Kuolleisuuden riskin eikuitenkaan todettu lisääntyneen valtimotiehyen hoitoihin liittyen.
Asiasanat: avoimen valtimotiehyen hoito, avoin valtimotiehyt, hyvin pieni keskonen,kohorttitutkimus, kuolleisuus, parasetamoli
To my family
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Acknowledgements This work was carried out in the Department of Children and Adolescents, Oulu
University Hospital and University of Oulu, during 2013–2018.
I wish to express my deepest gratitude to my supervisors, Professor Mikko
Hallman and Docent Timo Saarela. Mikko, your knowledge of research is very
fascinating and I truly admire your long and successful international career as a
scientist. Timo’s sharp clinical skills have delighted me during these years at
NICU. No matter if it is day or night, you have always given me an answer to any
clinical problem. Thank you Timo, you have taught me so much about
neonatology. I would like to offer my special thanks to Docent Päivi Tapanainen,
Head of the Division of Paediatrics and Gynaecology, for nice discussions and the
benevolence towards me during these years. I wish to thank Professor Mika
Rämet for providing me good facilities for the clinical research. I am deeply
grateful for my first teacher in the field of neonatology, Docent Marja-Leena
Pokela. I also want to thank Mikko Remes for your essential guidance and
teaching which I received as a young doctor. I am grateful for Professor Matti
Uhari for introducing me to the world of EBM. These repeated lessons finally
reached the target.
I sincerely thank the official referees of the thesis, Docent Tiina Ojala and
Viena Tommiska, for their wise and constructive comments.
Special thanks go to Tytti Pokka for her eternal patience and guidance with
the statistics. Tytti, without you I would still sit in front of my computer staring at
the wonderful SPSS software and the everlasting epidemiological files. My
closest co-authors Outi Aikio and Docent Riitta Marttila earn my deepest
gratitude. I thank all the members of the follow-up group, Docent Terhi
Tapiainen, Docent Tuula Kaukola, and Docent Matti Nuutinen for your great
advices on my research. Tuula, my roommate at work, your kindness and wise
advice served with chocolate have been very important and sometimes even
lifesaving. Special thanks go to Docent Marita Valkama for teaching me both
neonatological skills and the very essential theoretical part. I wish to thank Antti
Härmä for your collegial attitude towards me during these years. All the rest of
the colleagues in the Department of Paediatrics at Oulu University Hospital which
I have worked with during these years, thank you. Special thanks go to Sami
Turunen, Merja Kallio and Docent Marja Ojaniemi.
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I wish to thank you the unbelievably nice, clever, funny and professional
nurses in the ward of our NICU. Riitta Vikeväinen, your work as study nurse in
the Preparas study was very important, thank you so much.
Kaikukuoro members, our choir has brought me so many joyful moments
during these years. I am so happy to have the music and this warm-hearted group
in my life, you ALL are important. My friends since childhood Tiina, Marja and
Kaisa, without you all I would not be me, in a positive way. My colleagues from
the Royal Prosecco Club, Mervi Linna and Johanna Uunila, have the great
privilege to be mentioned as royal ladies, you are all that and so much more,
thank you for everything. You are awesome ladies and fantastic human beings. I
owe my deepest gratitude to my colleagues and friends Docent Outi Peltoniemi,
and Katariina Mankinen. You have always been there, I am deeply grateful for
you both of our close friendship. My precious colleague and dear friend Efthymia
Protonotariou we have had so warm and nice relationship during these years
despite of the distance. Thank you Efi for your hospitality, kindness and the
fantastic philosophical discussions we have had over the years.
This life would be empty, lonely and senseless without my family. My
parents, my mother and my late father always believed in me and supported me,
thank you so much. You offered me a great childhood with so many activities,
which gave me a wide perspective to life itself. Mother, you were always there
when I needed you, thank you. I want to thank my brother Ismo and my sister
Päivikki for everything. The whole sister’s family, you all are so awesome and
fantastic people! My beloved children Paavo and Tatu, you have shown me the
true meaning of life and love, thank you both of my precious ones. Mother loves
you so much. And finally, thank you dear Mika so much for everything. Our first
years with children and the sudden losses of our close ones were not the easiest
ones, but finally we survived after all those heavy years. This is a true merit!
This work was supported financially by the Alma and K.A. Foundation, the
University of Oulu Graduate School, the Foundation of Paediatric Research and
the Medical Research Center, Oulu.
Oulu, September 2018 Pia Härkin
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Abbreviations AA arachidonic acid
APAP acetyl-para-aminophenol
BW birth weight
BNP brain natriuretic peptide
BPD bronchopulmonary dysplasia
CI confidence intervals
CLD chronic lung disease
COX cyclooxygenase
DA ductus arteriosus
ECHO echocardiography
ELGA extremely low gestational age (< 28 weeks)
GA gestational age
hsPDA hemodynamically significant patent ductus arteriosus
IV intravenous
IVH intraventricular haemorrhage
LA/Ao left-atrium-to-aorta ratio
LPA left pulmonary artery
MCA middle cerebral artery
MPA main pulmonary artery
NAPQI N-acetyl-p-benzoquinone-imine
NDI neurodevelopmental impairment
NEC necrotising enterocolitis
NSAID non-steroidal anti-inflammatory drug
NNT number needed to treat
NT-proBNP amino-terminal pro-B-type natriuretic peptide
OR odds ratio
PAH pulmonary arterial hypertension
PDA patent ductus arteriosus
PG prostaglandin
PGE2 prostaglandin E2
PLCS post-ligation cardiac syndrome
PROM premature rupture of the foetal membranes
PVL periventricular leukomalacia
RCT randomised controlled trial
RDS respiratory distress syndrome
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ROP retinopathy of prematurity
RR relative risk
SD standard deviation
SGA small for gestational age
VLGA very low gestational age (< 32 weeks)
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List of original articles This thesis is based on the following publications, which are referred throughout
the text by their Roman numerals:
I Aikio O., Härkin P., Saarela T., & Hallman M. (2014). Early paracetamol treatment associated with lowered risk of persistent ductus arteriosus in very preterm infants. J Matern Fetal Neonatal Med, 27(12), 1252-6.
II Härkin P., Härmä A., Aikio O., Valkama M., Leskinen M., Saarela T. & Hallman M. (2016). Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. J Pediatr. 177, 72-77.e2.
III Härkin P., Marttila R., Pokka T., Saarela T., & Hallman M. (2017) Morbidities associated with patent ductus arteriosus in preterm infants. Nationwide cohort study. J Matern Fetal Neonatal Med. 11, 1-8. doi: 10.1080/14767058.2017.1347921.
IV Härkin P., Marttila R., Pokka T., Saarela T., & Hallman M. (2018). National survival analysis of infants born extremely preterm. Manuscript.
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Table of contents Abstract
Tiivistelmä
Acknowledgements 9 Abbreviations 11 List of original articles 13 Table of contents 15 1 Introduction 17 2 Review of the literature 19
2.1 Physiology and pathophysiology of the ductus arteriosus ...................... 19 2.2 The incidence of patent ductus arteriosus (PDA) .................................... 20 2.3 Diagnosis and definition of hemodynamically significant PDA ............. 21
2.3.1 Echocardiography (ECHO) .......................................................... 21 2.3.2 Clinical diagnosis of hsPDA in very preterm infants ................... 22 2.3.3 Postnatal age of ductal ECHO screening for treatment ................ 22 2.3.4 Biochemical markers .................................................................... 23
2.4 Treatment of PDA ................................................................................... 23 2.4.1 Treatment challenges .................................................................... 23 2.4.2 Conservative management of PDA .............................................. 24 2.4.3 Medical treatment of PDA ............................................................ 25 2.4.4 Surgical ligation of PDA .............................................................. 28 2.4.5 Other options for the treatment ..................................................... 29
2.5 Postnatal age for PDA treatment ............................................................. 30 2.5.1 Prophylactic and early treatment .................................................. 30 2.5.2 Late treatment (symptomatic therapy) .......................................... 31 2.5.3 Optimal postnatal age for treatment ............................................. 31
2.6 Paracetamol (acetaminophen) ................................................................. 32 2.6.1 Paracetamol for pain in preterm infants ....................................... 32 2.6.2 Paracetamol for patent ductus arteriosus ...................................... 35 2.6.3 Side effects of paracetamol ........................................................... 38
2.7 Association of the treatments of PDA with neonatal morbidities ........... 39 2.7.1 Associations with bronchopulmonary dysplasia (BPD) ............... 40 2.7.2 Associations with other neonatal outcomes and mortality ........... 41
3 Aims of the research 43 4 Patients and methods 45
4.1.1 Paracetamol for patent ductus arteriosus (I and II) ....................... 45
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4.1.2 Morbidities and mortality associated with PDA treatments
(III) ............................................................................................... 49 4.1.3 National survival analysis of infants born extremely
preterm (IV). ................................................................................. 52 5 Results 53
5.1 Paracetamol for patent ductus arteriosus ................................................. 53 5.2 Morbidities and mortality associated with PDA treatments (III) ............ 57 5.3 Mortality of infants born extremely preterm (IV) ................................... 61
6 Discussion 65 7 Conclusions 69 References 71 Original publications 85
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1 Introduction The rate of preterm birth varies globally, occurring in 5–18% of all births and
contributing significantly to infant mortality and morbidity (Blencowe et al.,
2012). Prematurity is the largest cause of neonatal death worldwide (Kong et al.,
2016; Liu et al., 2016). The risk for mortality and morbidity is highest in infants
born extremely preterm, under i.e. less than 28 weeks of gestation (EXPRESS
Group et al., 2009; Serenius et al., 2014). Mortality and morbidity rates of very
preterm infants differ between regions and countries (Boghossian, Geraci,
Edwards, & Horbar, 2018; Bonet et al., 2017; Edstedt Bonamy et al., 2018;
Serenius et al., 2014).
Level of immaturity is the main contributing factor to later neonatal morbidity,
such as retinopathy of prematurity (ROP), necrotising enterocolitis (NEC),
intraventricular haemorrhage (IVH), and bronchopulmonary dysplasia (BPD).
However, the importance and the independent role of the patent ductus arteriosus
(PDA) in the later management and survival of preterm infants are controversial
and unclear. Therapies used for the closure of PDA are either medical (ibuprofen
or indomethacin) or surgical, but these therapies have potential side effects for
premature infants (R. I. Clyman & Chorne, 2007; Janz-Robinson et al., 2015;
Madan, Kendrick, Hagadorn, Frantz, & National Institute of Child Health and
Human Development Neonatal Research Network, 2009). There is no consensus
regarding either the criteria of hemodynamically significant patent ductus
arteriosus (hsPDA) or the optimal postnatal age of treatment (Jain & Shah, 2015;
Skelton, Evans, & Smythe, 1994; Zonnenberg & de Waal, 2012).
Previous case reports and observational studies have shown that paracetamol
may be an alternative to the closure of PDA (Allegaert, 2013; Aminoshariae &
Khan, 2015; Hammerman et al., 2011; Oncel et al., 2013). Several recent
randomised controlled trial (RCT) studies also show that paracetamol may be as
effective as ibuprofen and indomethacin for closing PDA of preterm infants, but
with fewer side effects. However, evidence of the indications, dosage,
effectiveness, and safety −including the long-term effects of paracetamol− are still
incomplete or lacking.
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2 Review of the literature
2.1 Physiology and pathophysiology of the ductus arteriosus
Patency of the ductus arteriosus (DA) is essential in the foetal period, as it
connects the main pulmonary artery (MPA) to the descending aorta (Ao) to
guarantee normal foetal circulation and development of the foetus. The DA
diverts ventricular output away from the lungs and towards the placenta (Hamrick
& Hansmann, 2010). Closure of the duct during the foetal period may lead to
foetal demise. In normal situations, the duct acts like a physiological shunt and
closes functionally by 72 hours of age in 90% of term infants (Gentile et al., 1981;
Skinner, Skinner, Alverson, & Hunter, 2000). Normally, the shunt pattern changes
left to right before complete closure (Skelton et al., 1994). In normal functional
closure of PDA, the wall of the vessel thickens, endothelial cells activate, and
smooth muscle cells contract. Vasodilatory agents drop (the main vasodilator is
PGE2) and contracting agents (e.g, oxygen level) rise, resulting in the vessel
contracting functionally (Hamrick & Hansmann, 2010). In normal situations, after
functional closure, the anatomical (final) closure takes place within three weeks
of age. In most preterm infants, the functional closure of PDA is immature and
delayed.
If the DA remains open for a prolonged period after birth, it can change from
a physiological to a pathophysiological shunt, or PDA. Prolonged patency of the
duct can be caused by structural, functional, immature, and altered physiological
conditions (Bokenkamp, DeRuiter, van Munsteren, & Gittenberger-de Groot,
2010). Because there is normal individual variation of neonatal cardiovascular
physiology and circulation changes during the transition period, the hemodynamic
diagnostics during the early postnatal time is challenging (Vrancken, van Heijst,
& de Boode, 2018). After normal postnatal decrease of high pulmonary pressure,
the shunt direction soon changes from right to left (foetal circulation) and
becomes left to right (from the aorta to the pulmonary artery) also in immature
infants. Normally, the shunt is diverted completely or predominantly in 95% of
preterm infants by 5 hours after birth in infants born under 30 gestation weeks
(Kluckow & Evans, 2000b). If PDA stays hemodynamically significantly open
(hsPDA), it may lead to overloading in the right side (pulmonary overcirculation)
and systemic hypoperfusion in the left side (low systemic blood flow) (R. I.
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Clyman, 2012). This change in circulation may induce symptoms in the infant
condition.
The right-side overloading via the ductal shunt may lead to pulmonary
problems, including prolonged need of mechanical ventilation, surfactant
inhibition, pulmonary oedema or haemorrhage and later, the risk of BPD and
death (Kluckow & Evans, 2000a). On the left side, systemic hypoperfusion may
lead to end-organ hypoperfusion and ischemia as a result of reduced renal and
mesenteric flow, reduced middle cerebral artery blood flow velocity, and,
thereafter, possible risk for NEC, IVH and periventricular leukomalacia (PVL)
(Evans & Iyer, 1994; Evans & Kluckow, 1996; Evans, 2015; Pladys et al., 2001).
Large PDA can sometimes lead to cardiac failure, but this, fortunately, is rare.
Association of PDA with later morbidities is not clear however, and does have
great individual variability. Comorbidities depend on the size of PDA, the degree
of immaturity, and the capacity of the compensatory mechanisms of the infant’s
hemodynamic system. For example, when cerebral autoregulation is disturbed,
the risk for IVH with PDA rises (Perlman, Hill, & Volpe, 1981; Van Bel, Van de
Bor, Stijnen, Baan, & Ruys, 1989). Even large PDA with low systemic blood
pressure combined with good cerebral autoregulation, does not necessarily
influence the infant’s prognosis. However, the single or independent role of PDA
and its relationship to later morbidities is not clear (Hamrick & Hansmann, 2010).
2.2 The incidence of patent ductus arteriosus (PDA)
In healthy term infants, the incidence of PDA is between 0.02% and 0.006% of
live births, with a 2:1 female-to-male ratio (Tripathi, Black, Park, & Jerrell, 2013).
The aetiology is suggested to be multifactorial, with some genetic component in
the pathogenesis (Bokenkamp et al., 2010; Tripathi et al., 2013). In preterm
infants, the occurrence of PDA is inversely related to gestational weeks. The more
premature the infant, the higher the incidence of PDA. In very low gestational age
(VLGA) infants (born < 32 weeks), more than 30% have PDA, and in those born
under 28 weeks, 55–70% are at risk for significant open ductus requiring
treatment (Reller, Rice, & McDonald, 1993). However, spontaneous closure is
frequent. By 7 days of life, about 80% of infants born between 26 and 31
gestational weeks had no or only small PDA (Van Overmeire, Van de Broek, Van
Laer, Weyler, & Vanhaesebrouck, 2001). In contrast, in the group of infants born
<25 gestational weeks, the proportion of spontaneous closure was only 12.5%,
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showing that the most immature infants are at the highest risk for PDA (Koch et
al., 2006).
2.3 Diagnosis and definition of hemodynamically significant PDA
2.3.1 Echocardiography (ECHO)
Colour Doppler heart echocardiography (ECHO) is used to measure the
hemodynamic significance and the volume of the ductal shunt (ductal size).
ECHO should be performed prior to closing the duct to reveal possible congenital
heart defect (Chu, Li, Kosinski, Hornik, & Hill, 2017) and related
contraindications for ductal closure. In case of ductal-dependent systemic or
pulmonary circulation, closing the duct can be life threatening for the infant. In
this case, prostaglandin analogues must be infused to keep the ductal vessel open.
The parameters and ECHO criteria for hsPDA are variable (Jain & Shah,
2015). There are criteria and scoring of hsPDA, but without clear consensus (A.
El-Khuffash et al., 2015; Sehgal, Paul, & Menahem, 2013; Skelton et al., 1994;
Su, Watanabe, Shimizu, & Yanagisawa, 1997). ECHO parameters commonly used
for hsPDA include PDA diameter (the internal size of the duct in two-dimensional
view > 1.5-2.0 mm or 2 mm/kg), the left-atrium-to-aortic root ratio (LA/Ao > 1.4),
internal ductal diameter > 50% wider than that of the left pulmonary artery,
velocity of the shunt < 2 m/s, and a flow pattern characterised by a large left-to-
right ductal shunt (Evans & Iyer, 1994; Skinner et al., 2000; Zonnenberg & de
Waal, 2012). In clinical practice, evaluating ductal flow and the vessel’s true
diameter is challenging because vessel dimensions vary (diameter is not static)
during the transitional period, especially in the most immature infants. There is
also anatomical and topological variance in the ductal architecture and viewing
three-dimensional structures in two-dimension ECHO requires experience and
expertise (Krichenko et al., 1989). Left-side (atrial or ventricular) dilatation
indicates that the ductus is hemodynamically significant. Large PDA for
prolonged time may lead to heart failure. Pressure gradient across PDA shows a
continuous flow profile from left to right, indicating a possible large- volume
shunt (Evans & Iyer, 1994; Skinner et al., 2000). Experienced
echocardiographists and paediatric cardiologists employ other detailed ECHO
parameters, such as pulmonary vein Doppler measurements and pulmonary
overcirculation measurements from left ventricular output overload. In
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large/moderate-volume ductal shunt systemic hypoperfusion (low systemic blood
flow), signs can be seen from absent or reversed diastolic flow from the middle
cerebral artery, the descending aorta, or/and the coeliac trunk artery (A. F. El-
Khuffash, Jain, & McNamara, 2013).
2.3.2 Clinical diagnosis of hsPDA in very preterm infants
The clinical criteria and symptoms of hsPDA in premature infants are classified as
a murmur, cardiopulmonary distress, hyperdynamic precordium, bounding pulses,
increased need for respiratory support, and wide pulse pressure. A PDA murmur
is continuous if there is a constant pressure gradient in both the systole and the
diastole as blood is forced via the duct from left to right (from the aorta into the
pulmonary artery). The aortic blood pressure must be higher than the pulmonary
pressure during diastole to cause the left to right shunt direction in the ductal flow.
McNamara’s criteria combine clinical signs and ECHO parameters (McNamara &
Sehgal, 2007). Another scoring system for PDA defines the significance of PDA
based on ECHO criteria (A. El-Khuffash et al., 2015). The challenge with these
definitions is that there is still no consensus for clinicians regarding hsPDA
criteria, which PDA should be treated, when, and how. In addition, the great
individual variation in premature infants’ hemodynamical adaptance to the PDA
shunt makes the criteria for treatment challenging for the clinician. Decisions
about therapy should be based on individual clinical signs of a large left-right
shunt with echocardiographic parameters showing hsPDA. Chest x-ray may also
show signs of increased pulmonary vasculature and notable heart dilatation in the
case of hsPDA.
2.3.3 Postnatal age of ductal ECHO screening for treatment
There are different approaches regarding the optimal postnatal age for ECHO
screening and the subsequent treatment procedures for PDA in preterm infants.
Potential approaches to PDA management are early screening, early targeted
intervention, or delayed intervention, which indicates a more conservative attitude.
Early screening (before day 3 of life) in extremely low gestational age (ELGA)
infants was associated with lower in-hospital mortality (number needed to treat
(NNT) to prevent one death = 23), but there were no differences between major
neonatal morbidities such as NEC, severe BPD, or severe cerebral lesions when
compared to unscreened infants (Roze et al., 2015). Performed on second
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postnatal day, cardiac ultrasound-targeted measures of PDA diameter and
maximum flow velocity in very preterm infants showed that a specific PDA
severity score is able to predict the later occurrence of chronic lung disease (CLD)
or death in the high-risk group (A. El-Khuffash et al., 2015). Early screening
entails a risk of overtreatment of PDA and a possible higher risk for adverse
effects associated with the treatment procedures. Early targeted intervention of
ductal closure is based mainly on shunt volume, and its benefits are the selection
of patients with an evolving shunt. The later or delayed (conservative)
intervention approach is based mainly on clinical assessment, and entails less
need for treatment but also a potential risk for later morbidity (risk for BPD) and
mortality associated with PDA itself.
2.3.4 Biochemical markers
Brain natriuretic peptide (BNP) and amino-terminal pro-B type natriuretic peptide
(NT-proBNP) are synthesised and released into the circulatory system by the
cardiac ventricular myocytes in response to pressure overload, volume expansion
and increased myocardial wall stress. Because the hemodynamic efficient of PDA
is occasionally difficult to comprehend with a sole ECHO, a simple blood test
would provide an attractive additional diagnostic tool for clinicians. Unfortunately,
studies have shown that the diagnostic accuracy of BNP and NT-Pro-BNP for
hsPDA are not valid for clinical decisions in the management of hsPDA of
premature infants (M. Kulkarni et al., 2015).
2.4 Treatment of PDA
2.4.1 Treatment challenges
Medical treatment with either indomethacin or ibuprofen and surgical closure
(PDA ligation) is the mainstay in the management of PDA. Of late, conservative
management has become a more popular choice of treatment. There is no
consensus of treatment (Evans, 2015), which reflects the holistic problem of
reconciling PDA in preterm infants with the continuing dilemma of diagnosing
and defining hsPDA. The Effective Perinatal Intensive Care in Europe (EPICE)
study (a population-based cohort study in 19 regions in 11 European countries
during 2011-2012 of all births born before 32 gestational weeks) noticed that
24
treatment policies of PDA treatments were very heterogenic. However, the
variation in PDA treatment did not explain differences in patient risk factors such
as mortality and severe BPD (Edstedt Bonamy et al., 2017). The independent role
of PDA and its association with later morbidities is not clear, and a more uniform
strategy is needed. The treatment of PDA is challenging as spontaneous closure is
frequent, and the solid evidence of treatment benefit is lacking. PDA treatment
trials (randomised controlled studies of PDA treatment) have not shown evidence
of a reduction in PDA-associated morbidities such as severe IVH, NEC, severe
BPD, death, and worsened neurodevelopmental outcome (Benitz, 2010; Benitz,
2012; R. I. Clyman & Chorne, 2007). The treatment of PDA and, especially the
early active closure of PDA and its association with later neonatal morbidity
remains inconclusive (A. El-Khuffash et al., 2015; Gudmundsdottir et al., 2015;
Schena et al., 2015; Slaughter, Reagan, Bapat, Newman, & Klebanoff, 2016;
Weisz, More, McNamara, & Shah, 2014). The EPICE study showed that the
proportion of PDA treatments varied from 10% to 39% (p < 0.001) between
(European) regions, indicating different management approaches (Edstedt
Bonamy et al., 2017).
2.4.2 Conservative management of PDA
The conservative treatment option means watchful waiting for spontaneous
closure of PDA. Recently, the trend of conservative management has become
more accepted approach (Benitz & Committee on Fetus and Newborn, American
Academy of Pediatrics, 2016). It has been shown that routine treatment to close
PDA, either medically or surgically, in the first two weeks after birth does not
improve long-term outcomes (level of evidence: 1A) (Benitz & Committee on
Fetus and Newborn, American Academy of Pediatrics, 2016). Neither clinical
trials nor meta-analyses have shown that closing the duct improves long-term
outcomes. Routine treatment, especially when conducted early on, has no effect
on morbidities like BPD, NEC, and mortality (Benitz, 2010). Prophylactic
indomethacin (given by 12 hours of life) seems to reduce the rate of severe IVH
and early severe pulmonary haemorrhage, but it did not improve long-term
neurodevelopmental or respiratory outcomes (Schmidt et al., 2001). Jhaveri et al.
(2010) reported a significantly lower rate of NEC in ELGA infants without
treatment of PDA (conservative management) when compared to infants treated
with early ligation after an attempt of indomethacin therapy (Jhaveri, Moon-
Grady, & Clyman, 2010). In a recent meta-analysis of different treatment options
25
for hsPDA (ibuprofen, indomethacin, paracetamol or placebo), placebo or no
treatment was not associated with an increased likelihood of mortality and
morbidity such as NEC or IVH (Mitra et al., 2018). On the contrary, a multicentre
cohort study of the most preterm infants (born < 1000 g, included infants n=494)
showed that a conservative approach towards PDA was associated with higher
mortality, whereas a surgical approach was associated with an increased
occurrence of BPD at 36 weeks and ROP. However, medical and conservative
treatments were protective for the outcome of death/BPD at 36 weeks (Sadeck et
al., 2014).
High fluid intake (> 170 mL/kg/day) during the first days of life in very
premature infants has been associated with an increased risk of PDA (Stephens et
al., 2008). Fluid restriction has been shown to predispose closure of the ductus,
thus constituting an important part of conservative PDA management. Optimal
fluid restriction in VLGA infants improves pulmonary function by decreasing the
overloading of pulmonary circulation (De Buyst, Rakza, Pennaforte, Johansson,
& Storme, 2012). In a systematic review, restricted fluid intake is associated with
a reduction in PDA (E. F. Bell & Acarregui, 2008). When the fluid volume is
restricted, adequate energy intake must be evaluated to ensure sufficient calorie
intake and avoid harming the premature infant’s optimal outcome. In practice, this
means adding energy supplies such as carbohydrates, protein, and fat to the diet to
prevent growth restriction.
The use of diuretics is not recommended for the treatment of PDA because
there is no evidence of benefits to PDA closure. Furthermore, side effects of these
drugs, especially to premature infants in their early days, could present more
drawbacks than advantages (Brion & Campbell, 1999; Ketkeaw, Thaithumyanon,
& Punnahitananda, 2004; B. S. Lee et al., 2010).
2.4.3 Medical treatment of PDA
Medical treatments for PDA closure in preterm infants include the
cyclooxygenase (COX) inhibitors ibuprofen and indomethacin. These drugs are
non-steroidal anti-inflammatory drugs (NSAIDs) that contract the duct by
inhibiting the formation of vasodilators such as prostaglandins (PGs) (Figure 1).
Inhibition occurs when the drugs influence the cyclooxygenase enzyme and block
the formation of PGs (mainly PGE2) from arachidonic acid (AA) (R. I. Clyman,
Saha, Jobe, & Oh, 2007; Ohlsson, Walia, & Shah, 2015; Sadeck et al., 2014).
Treatment success is about the same (70−80%) for both ibuprofen and
26
indomethacin (Gournay et al., 2004). ELGA infants, in whom the occurrence of
hsPDA is highest, present the most challenging and problematic group for
medical treatment. The efficiency of the drug is generally worse in ELGA infants
than in more mature infants. Furthermore, due to immaturity, the frequencies of
other comorbidities, and the risks of side effects due to treatments are higher in
these high-risk infants. Another dilemma is that a meta-analysis of more than 50
RCT studies found no long-term benefits regarding NSAID treatments in preterm
infants (Benitz, 2010; Benitz, 2012).
Indomethacin
Indomethacin is an NSAID that inhibits COX enzymes and prevents the
formation of PGs from AA (Figure 1). It was first described in 1976 for the
closure of PDA in premature infants (Friedman, Hirschklau, Printz, Pitlick, &
Kirkpatrick, 1976; Heymann, Rudolph, & Silverman, 1976). Indomethacin is the
most widely used COX-inhibitor for PDA closure until now. Slightly different
dose regimens, varying between 0.1 and 0.2 mg/kg every 24-hours and usually for
three doses have been used to treat PDA (Mezu-Ndubuisi et al., 2012). A
prolonged course (> 4 doses) has also been used, but a large meta-analysis of 431
infants noticed no difference in PDA closure, re-treatment or ligation rates when
compared to a short course. Furthermore, there was an increased risk for NEC,
RR 1.87 (95% CI 1.1–3.27), in groups in which prolonged indomethacin courses
were administrated (Herrera, Holberton, & Davis, 2007).
Early prophylactic indomethacin has been shown to reduce periventricular or
intraventricular haemorrhage but does not improve later neurodevelopmental
outcome. In a multicentre double-blinded RCT trial, infants born before 29 weeks
of gestation with large PDA (“high-risk group”) were randomised to receive
either indomethacin (n=44) or a placebo (n=48). Infants were screened by
ultrasound and the study drug was started by 12 hours of age (prophylactic
treatment). Infants in the indomethacin group had significantly less pulmonary
haemorrhage (2% vs 21%) and a trend of less IVH (4.5% vs 12.5%), but the latter
was statistically not significant. The infants with small PDA (not randomised
infants) had a lower risk of pulmonary haemorrhage, and 80% of those had
spontaneous PDA closure, indicating that an early and precise diagnosis of ductal
shunt volume is important when making the decision about therapy (Kluckow,
Jeffery, Gill, & Evans, 2014). Indomethacin treatment is associated with renal
impairment (Lin et al., 2017) and gastrointestinal complications; the risk being
27
even stronger if an infant is simultaneously receiving corticosteroids or
nephrotoxic drugs (e.g, aminoglycosides). In a RCT study of extremely low birth
weight infants with significant PDA, the indomethacin group (n=73) received the
dose 0.2+0.1+0.1 mg/kg every 24 hours as compared with the ibuprofen group
(n=71) which received the dose 10+5+5 mg/kg every 24 hours. Indomethacin was
more effective than ibuprofen at closing PDA (66% vs 49%, p= 0.046). However,
renal side effects were more common in the indomethacin group (e.g, higher
creatinine, lower glomerular filtration, lower urinary output) than in the ibuprofen
group. There was no difference in other neonatal morbidities (BPD, IVH, NEC,
and ROP) or mortality between the groups (Lin et al., 2017).
Ibuprofen
Ibuprofen is a nonselective COX-inhibitor that reduces PG-mediated
vasodilatation (Figure 1). It is administrated intravenously or orally, and various
dosing regimens have been proposed. The standard dose of ibuprofen is given
over three days (three doses): 10 mg/kg/day followed by 5 mg/kg/day at 24-hour
intervals for two days (IV and oral administrations) (Van Overmeire, Touw,
Schepens, Kearns, & van den Anker, 2001). Higher doses comprise 15–20 mg/kg
followed by 7.5–10 mg/kg administered every 12 to 24 hours for a total of three
doses (IV and oral); repeated courses have also been used (Dani et al., 2012;
Mitra et al., 2018).
There is some evidence that orally administered ibuprofen is as effective as
IV ibuprofen for PDA closure (Ohlsson et al., 2015; Oncel & Erdeve, 2016).
When compared, oral ibuprofen was as efficacious as IV indomethacin in closing
PDA, and easier to administrate (Aly et al., 2007). In a meta-analysis (68 RCT
studies with 4,802 infants), the effects of indomethacin, ibuprofen and
paracetamol to close hsPDA were studied. A high dose of oral ibuprofen was
associated with the highest likelihood of hsPDA closure, versus standard doses of
IV ibuprofen or IV indomethacin (Mitra et al., 2018). However, high-dose
ibuprofen presents a higher risk of potential side effects, especially in the most
immature infants. Because of the nonselective mechanism of COX-inhibitors,
ibuprofen can cause side effects that include gastrointestinal bleeding, NEC and
pulmonary hypertension. Risks for gastrointestinal side effects are greater when
ibuprofen is combined with cortisone treatment (Peltoniemi et al., 2005). The risk
for pulmonary arterial hypertension (PAH) following ibuprofen treatment is
highest in low gestational age infants and when prenatal risk factors such as small
28
for gestational age (SGA), maternal hypertension of pregnancy or
oligohydramnion are present (Kim et al., 2016). However, ibuprofen generally
has a better safety profile when compared to indomethacin (Ohlsson et al., 2015).
2.4.4 Surgical ligation of PDA
Surgical ligation of PDA is effective in definitively interrupting the ductal shunt.
Most premature infants who require surgical treatment for PDA are the most
immature (less than 28 gestational weeks) and the sickest, typically with
hemodynamic instability and respiratory insufficiency. Most have had medical
treatment (NSAID) prior to ligation if there has been no contraindication for
medical treatment, such as IVH (Weisz & Giesinger, 2018). The past 10 years
have seen a reduction in ligation rates due to a more conservative approach of
treating PDA (Benitz & Committee on Fetus and Newborn, American Academy
of Pediatrics, 2016) and the concern of side effects related to the procedure.
However, treatment options vary globally between centres and countries. In the
United States, for example, direct surgical ligation in ELGA infants has been
more frequent than in the United Kingdom (A. Kulkarni, Richards, & Duffy,
2013). There is also great variability between centres: California hospital ligation
numbers range from 0% to 67% (H. C. Lee, Durand, Danielsen, Duenas, &
Powers, 2015).
While effective, ligation has been associated with both short and long-term
adverse neonatal outcomes, including post-ligation cardiac syndrome (PLCS),
vocal fold paralysis, pneumothorax, chylothorax, and later neurosensory
impairment in early childhood (A. F. El-Khuffash, Jain, Weisz, Mertens, &
McNamara, 2014; Gould et al., 2003; Ibrahim et al., 2015; Jhaveri et al., 2010;
Ting et al., 2016; Weisz et al., 2014). The independent role of ligation and its
association with later problems are unclear; because ligated infants are usually the
most immature and the sickest, the causality to adverse outcomes is unsure. Most
ligated immature infants have one or several related morbidities simultaneous
with prematurity, such as respiratory distress syndrome (RDS) (with mechanical
ventilation), IVH, BPD, ROP and NEC, and therefore the independent role of
PDA and its treatment in later morbidity and mortality is not clear, and causality
is difficult to show. Thus, a selection bias may exist in studies that compare
ligated and non-ligated infants and their later outcomes. There are also studies
where ligation (either direct or after failed medication therapy) has not been
associated with increased mortality or neurodevelopmental impairment (NDI)
29
when compared to conservative management alone (Weisz et al., 2018). In some
studies, mortality rates in ligated group have been associated with a lower risk of
in-hospital mortality (Weisz et al., 2018). On the other hand, surgical ligation in
VLGA infants seemed to increase the risk of BPD, ROP laser treatment, longer
hospital stay, and longer mechanical ventilation when compared to un-ligated
group (Youn, Moon, Lee, Lee, & Sung, 2017).
Different results show the heterogeneity of the issue and the difficulty of
demonstrating cause-consequence of the ligation and later outcomes, especially in
retrospective and epidemiological studies. However, PLCS after ligation has been
associated with both a higher risk of mortality and a risk of neurodevelopmental
problems later. PLCS may worsen hemodynamic instability and oxygenation (A.
F. El-Khuffash et al., 2014). The optimal selection of patients and the timing of
ligation are key to minimising the procedure’s side effects. The careful selection
of patients for PDA ligation and systematic triage has been shown to reduce the
number of PDA ligations (24% of referrals for surgery were cancelled) without
impacting short-term neonatal morbidity (Resende et al., 2016).
2.4.5 Other options for the treatment
Percutaneous or catheter-based closure has been used to treat PDA for more than
50 years in term neonates (Portsmann & Wierny, 1978). However, the success and
safety of this treatment in very preterm infants is unclear, and has not become
treatment of choice. The procedure has potential future value for premature
infants because it may have fewer complications than surgical ligation. Risks
defined in catheter-based closure are acute arterial injury and aortic or left
pulmonary artery (LPA) obstruction (Backes et al., 2016; Zahn et al., 2016). In a
retrospective analysis performed over a 10-year period at a single centre (n=52),
PDA closure in very preterm infants weighing less than 4 kg was successful in 88%
of the infants. In extremely premature infants (n=24) the successful rate for
transcatheter closure of PDA was also 88% (3/24 failed) (Zahn et al., 2016). A
less invasive procedure is an attractive alternative over surgical ligation, but more
studies are still needed.
30
2.5 Postnatal age for PDA treatment
The optimal postnatal age for PDA closure is unclear. The timing of medical
treatment has ranged from prophylactic and early treatment at the very first
postnatal days to later treatment at several weeks or even months of age.
2.5.1 Prophylactic and early treatment
Prophylactic treatment of PDA refers to closure of the ductus before 12− 24 hours
of life and before the onset of symptoms in all at risk preterm infants. Previous
trials of prophylactic indomethacin and ibuprofen seemed to decrease the risk of
PDA but caused significant side effects and did not decrease overall morbidity
and mortality (Gournay et al., 2004; Kluckow et al., 2014; Schmidt et al., 2006).
Although prophylactic indomethacin has been shown to reduce the rate of severe
(grades 3 and 4) IVH and pulmonary haemorrhage, it has not demonstrated a
reduction in later morbidities such as BPD, ROP, and NEC, and no improvement
in survival (Schmidt et al., 2006). Indomethacin treatment of large PDA (> 1.7
mm) before 12 hours of age reduced the incidence of pulmonary haemorrhage (9%
vs 23%) and the need of later treatment of PDA (20% vs 40%) but had no effect
on the primary outcome of death or adverse cranial ultrasound findings (Kluckow
et al., 2014). A meta-analysis of prophylactic IV indomethacin found no
improvement in long-term neurodevelopmental outcome or mortality (Fowlie,
Davis, & McGuire, 2010; Schmidt et al., 2001). Prophylactic ibuprofen treatment
has also been tested in preterm infants. Unfortunately, the significantly increased
risk of pulmonary hypertension was found to associate with this approach.
Prophylactic ibuprofen treatment has since been abandoned (Gournay et al., 2004).
In conclusion, prophylactic medical treatment for PDA is not recommended
because of its side effects and because it poses no benefit for later morbidity and
mortality (Cotts, 2009; Ohlsson & Shah, 2011).
Prophylactic or early ligation is not considered a valid treatment for the same
reason and has been abandoned. If surgical closure is performed early, when a
premature infant’s hemodynamic system is both fragile and labile, the risks for
complications rise both during and after the operation. Surgical closure of PDA
may induce a rapid increase in previously low cerebral perfusion as a result of
shunting blood to pulmonary circulation. This, in combination with the fragile
vasculature of the germinal matrix and the potential for reperfusion injury, is
likely to predispose the infant to IVH (Soleymani, Khoo, Noori, & Seri, 2015).
31
One strategy to prevent hsPDA is early treatment to close the duct very soon
after its diagnosis. In this approach, drug treatment is started before 7 days of life.
Because there is no evidence of benefits, this approach is not recommended by
most neonatologists. Early ibuprofen treatment (median age of 3 days) in VLGA
infants did not have any benefits over delayed treatment (Sosenko, Fajardo,
Claure, & Bancalari, 2012). A standard dose of IV ibuprofen therapy within 72
hours of birth in ELGA infants was effective to close the duct but resulted in no
benefits in later outcomes (e.g, NEC, IVH, BPD, and ROP) (Aranda et al., 2009).
2.5.2 Late treatment (symptomatic therapy)
The criteria and postnatal age for late treatment vary, but late treatment refers to
treatment after 7 days of life. This approach allows for possible spontaneous
closure of the open ductus. The treatment is usually started after hsPDA
symptoms appear or if there is a criterion of hemodynamic significance in
ultrasound. Conservative treatment sometimes refers to treatment even after
discharge. Studies have shown that surgical ligation in VLGA infants before 14
days of life increases the rates of ROP laser treatment, BPD, longer hospital stay
and longer mechanical ventilation when compared to the non-ligated group
(Gudmundsdottir et al., 2015; Youn et al., 2017).
2.5.3 Optimal postnatal age for treatment
The hsPDA should be closed, but what is the optimal time for closure? Premature
closure should be avoided, as possible side effects from the treatments are usually
greater than the shunt effect. The current evidence does not support prophylactic
or early (presymptomatic) closure. At the earliest, the ductal shunt should be
closed after it has turned completely left-to-right. In the case of pulmonary
hypertension (right-to-left shunt) or a ductal cross shunt (pulmonary and systemic
pressure of about the same magnitude), closing the duct can lead to right
ventricular failure. The optimal postnatal age for active ductal closing after the
shunt flow has turned remains controversial. Different trials are inconclusive
regarding when to treat the open ductus, as closing the duct has not affected the
outcomes of other severe neonatal morbidities (e.g, severe BPD, ROP, NEC, and
IVH). The majority of hsPDA cases appear in ELGA infants, who frequently
develop moderate-to-large PDA. Premature closure should be avoided because of
the risk for complications from the treatments, and too-late closure can increase
32
the risk for morbidities associated with left-to-right shunt. A trial of early vs late
ibuprofen treatment without hsPDA resulted in otherwise similar outcomes, but
early ibuprofen treatment was associated with worse respiratory outcome
(Bancalari, 2016; Bancalari & Jain, 2017; Sosenko et al., 2012).
The individual approach may be the most valid approach for treating PDA.
Treatment choice and postnatal age at treatment should be based on a
pathophysiology-based approach, where the clinical signs of hsPDA, ECHO signs
of hsPDA, and the possible side effects of treatments are evaluated and weighed.
The main dilemma of optimal closing time is that even if the duct is actively
closed, causality to morbidities associated both with the ductal shunt and the
therapies is unclear. Because of the heterogeneity of studies and protocols, it is
difficult to show the long-term benefits of the single therapies. Therefore, the
precise optimal time for treatment is challenging to determine. If the ductal shunt
is small and without harm to the infant, it favours conservative management, but
if it is large and causes severe symptoms such as ventilator problems, pulmonary
haemorrhage or hemodynamic lability, it should be closed. Premature and routine
treatment should be avoided; instead an individual approach should be employed
to evaluate the individual compensatory mechanisms of hemodynamics.
2.6 Paracetamol (acetaminophen)
2.6.1 Paracetamol for pain in preterm infants
Paracetamol (acetaminophen or N-acetyl-p-aminophenol, APAP) is an antipyretic
NSAID used to treat mild to moderate pain in premature infants. Like COX -
inhibitors, the drug inhibits the conversion of arachidonic acid (AA) to
prostaglandins (PGE2, PGI2). Paracetamol acts by lowering cyclooxygenase
products, but the precise mechanism of its action is unclear (Lucas, Warner,
Vojnovic, & Mitchell, 2005).
33
Fig. 1. Ibuprofen, indomethacin, and paracetamol in the arachidonic acid pathway. COX- inhibitors ibuprofen and indomethacin inhibit the cyclooxygenase (COX) part of prostaglandin. Paracetamol inhibits the peroxidase moiety of the enzyme, decreasing prostaglandin synthesis. Both sides must be active in the prostaglandin synthase enzyme to have the catalysing action.
Paracetamol may also inhibit the descending serotonergic pathways and inhibit
prostaglandin synthesis in the central nervous system. It also may have an active
metabolite influence on cannabinoid receptors (Pacifici & Allegaert, 2014). A
simplified model of the effect of paracetamols on the AA pathway is shown in
Figure 1. Unlike ibuprofen and indomethacin, paracetamol acts on the peroxidase
region of the prostaglandin synthase enzyme, resulting in a decrease in PG
synthesis (Anderson, 2008; Veyckemans, Anderson, Wolf, & Allegaert, 2014).
Paracetamol is primarily eliminated by hepatic metabolism, and hepatic
maturation is the key in paracetamol pharmacokinetics. Paracetamol undergoes
both sulfation and glucuronidation, and these nontoxic products are excreted
renally. In neonates, the sulfation of paracetamol predominates. Paracetamol also
undergoes oxidation by cytochrome P450 (CYP) enzymes, predominantly
CYP2E1, to form the reactive N-acetyl-p-benzoquinone-imine (NAPQI), which is
detoxified by conjugation with glutathione (Figure 2) (Cook, Roberts et al., 2016;
Cook, Stockmann et al., 2016). Repeated paracetamol administration has no effect
on glutathione plasma levels in the preterm infant, potentially reflecting good
glutathione stores.
34
Fig. 2. Paracetamol (acetaminophen) metabolism main pathways. In preterm infants, sulfation predominates, while the proportion of glucuronidation increases later in childhood and adults. Paracetamol is metabolised primarily in the liver into nontoxic* and toxic** products. Nontoxic products have renal excretion, while toxic NAPQI binds to liver proteins and amino acids. NAPQI production is primarily metabolised by the CYP2E1 pathway, and liver toxicity depends on NAPQI levels, not paracetamol itself.
In studies of paracetamol pharmacokinetics of premature infants, the dose of
paracetamol depends of the gestational age, but patient size (weight) is the major
covariate of clearance variance in neonates (Allegaert, Palmer, & Anderson, 2011).
Volume distribution in premature infants at 27 gestational weeks is 0.64 L/Kg,
reaching the mature value at about 6 months of age (0.4–0.45 L/kg). The
increased volume of distribution in neonates supports the use of a larger initial
dose (loading dose) of 20 mg/kg intravenously to attain paracetamol threshold
concentration sooner (10−20 mg/L) (Veyckemans et al., 2014; Wang et al., 2013).
After the loading dose, the maintenance dose is given, usually a repeated dose of
7.5−10 mg/kg/q6h. The clearance of paracetamol in neonates is one-third of the
mature value reported in adults. Clearance maturation is slow until 40 weeks of
gestation and matures rapidly to reach 90% of adult capacity in the first year of
life (Allegaert et al., 2011; Allegaert, Naulaers, Vanhaesebrouck, & Anderson,
2013; Pacifici & Allegaert, 2014; Wang et al., 2013). However, precise data
35
regarding the pharmacodynamic of paracetamol in the most immature infants are
still limited.
2.6.2 Paracetamol for patent ductus arteriosus
The use of paracetamol for closure of PDA in preterm infants was first published
in a small case report in 2011 (Hammerman et al., 2011). In that study, oral
paracetamol was given to five premature infants, after which all ducts closed.
Following this promising study, many observational studies were published,
showing that paracetamol could be an alternative for the closure of PDA in
preterm infants (Oncel et al., 2013; Terrin et al., 2016). Thereafter in prospective
RCT studies, paracetamol has been noted to have a closing effect on the DA in
premature infants (Dang et al., 2013; El-Mashad, El-Mahdy, El Amrousy, &
Elgendy, 2017; Oncel et al., 2014). Unlike indomethacin and ibuprofen,
paracetamol has no peripheral vasoconstrictive effect and has fewer side effects
(e.g, gastrointestinal). It would thus provide a more attractive choice for closure
of PDA than indomethacin and ibuprofen.
Primarily, paracetamol is administered to preterm infants intravenously. The
general dose used to treat PDA (15 mg/kg/6q) is greater than that used for pain
and antipyretics (7.5−10 mg/kg/6q). The efficacy of paracetamol has been
compared to COX-inhibitors, and it has been noted to be comparable with
indomethacin and ibuprofen. Both IV and oral paracetamol have been compared
to placebo and COX-inhibitors (IV indomethacin, IV or oral ibuprofen).
Paracetamol has been shown to be as effective as COX-inhibitors ibuprofen and
indomethacin, but with fewer side effects (El-Mashad et al., 2017; Oncel et al.,
2013; Terrin et al., 2016).
Oral and IV paracetamol have been shown to be equally effective (Dang et al.,
2013; Oncel et al., 2014). Although there are challenges in oral route
administration in very preterm infants during their first postnatal days, some
promising studies have shown that oral administration may be a safe and efficient
treatment for PDA (Dang et al., 2013; Oncel & Erdeve, 2016). RCTs have shown
that oral paracetamol is as effective as oral ibuprofen for the treatment of PDA in
infants born preterm, no significant differences between the secondary outcomes
were found (Al-Lawama, Alammori, Abdelghani, & Badran, 2018; Dang et al.,
2013; Ohlsson & Shah, 2015; Oncel et al., 2014). However, paracetamol
metabolism (e.g., peak concentrations and clearance) has been studied mainly in
36
IV forms. Because enteral paracetamol metabolism differs from the IV route,
dosage and safety of oral paracetamol for PDA need more prospective studies.
37
Tabl
e 2.
Ran
dom
ised
, con
trol
led
tria
ls o
f par
acet
amol
for p
aten
t duc
tus
arte
riosu
s
Stu
dy
Trea
tmen
t
grou
ps
Stu
dy
desi
gn
Par
acet
amol
dose
Ibu/
indo
dose
Pat
ient
s
(par
a/ib
u/in
do)
Pos
tnat
al
age
drug
star
ted
GW
Res
ults
(duc
tus
clos
ed a
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cour
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(%)
Mai
n
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lt
Sid
e ef
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s
Dan
g
2013
Po
para
/
Po
ibu
RC
T,
not
blin
ded
15 m
g/kg
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3 da
ys
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g/kg
for 3
day
s
160
(80/
80)
≤14
d ≤3
4 P
ara/
ibu
65(8
1.2%
)/63(
78.8
%)
p=0.
693,
RR
0.8
3 (0
.60−
1.15
)
Par
a as
effe
ctiv
e
as ib
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Par
a ha
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ss
hype
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2014
po p
ara
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po ib
u
RC
T 15
mg/
kg/6
h
3 da
ys
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90 (4
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)1 48
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h ≤3
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38
Serum concentrations of paracetamol should be about 10−20 mg/L to have
antipyretic and analgesic effect (Allegaert et al., 2013; Wang et al., 2013).
Therapeutic paracetamol levels for closure of the ductus are unknown. In one
small (n=10) retrospective pilot study of hsPDA closure with enteral paracetamol
treatment (15 mg/kg 4 times/day for 3 days) in premature infants (less than 34
weeks), a higher paracetamol concentration correlated with short-term ductal
response. If the concentration was below 20 mg/L, there was no response in PDA,
showing that the concentration needed to close PDA might be higher than the
target used for pain (Bin-Nun, Fink, Mimouni, Algur, & Hammerman, 2018).
Further studies are needed to define a precise dose of paracetamol used for
treating PDA.
2.6.3 Side effects of paracetamol
Acute and short-term safety of paracetamol is well documented. The drug is
known to have possible acute side effects on the liver. Especially when
administrated in high doses, elevations of liver enzymes have been seen.
Fortunately, the true hepatotoxicity caused by paracetamol is rare in neonates. It is
generated through the production of N-acetyl-p-benzoquinone-imine (NAPQI) by
the hepatic cytochrome P450 (Allegaert et al., 2011; Palmer et al., 2008).
Paracetamol-induced hepatotoxicity is not associated with exposure to the drug
per se but depends more of the amount of exposure to NAPQI and the amount of
protecting agent glutathione stores. In an extreme case report, a premature infant
born at 25 gestational weeks had accidentally received more than a 30- to 60- fold
overdose of paracetamol (446 mg/kg IV). An antidote (a glutathione precursor, N-
acetylcysteine) was given, and the infant survived without side effects (Porta,
Sanchez, Nicolas, Garcia, & Martinez, 2012). One hypothesis for the lack of
acute paracetamol toxicity in preterm infants is that, due to their immaturity, the
production of toxic metabolites (NAPQI) in the liver is low, while the synthesis of
protecting agents such as glutathione in the liver is mature, and thus formation
and stores are good despite prematurity.
Recent studies suggest a potential association between maternal paracetamol
exposures and possible foetal and, later, postnatal side effects for children. Safety
data concerning the long-term side effects of paracetamol use in the neonatal
period are limited. Epidemiological studies have shown that the maternal use of
analgesics in the second trimester or later could be associated with male
reproductive disorders such as cryptorchidism or hypospadias (Fisher et al., 2016;
39
Kilcoyne & Mitchell, 2017; Snijder et al., 2012). A possible explanation may be
that this affects steroidogenesis and, consequently, results in reduced androgen
(testosterone) production in the foetal testes. In-utero paracetamol side effects
were stronger if exposure occurred during the second trimester and if the mother
was taking the drug for a long term (> 4 weeks). However, the current evidence
regarding foetal exposure to paracetamol and later male reproductive disorders
cannot be concluded directly. The effect of paracetamol use, both in the neonatal
period and later in childhood, on the male testis is unknown.
There is no solid evidence that paracetamol could close the foetal duct when
administered in high (even toxic) doses (Taney, Anastasio, Paternostro, Berghella,
& Roman, 2017). There is one case report of ductal closure in near-term infants
due to maternal self-medication with nimesulide and paracetamol (Simbi,
Secchieri, Rinaldo, Demi, & Zanardo, 2002). The possible association between
paracetamol use during pregnancy and later adverse neurodevelopmental
outcomes has risen in recent studies (Bauer, Kriebel, Herbert, Bornehag, & Swan,
2018). Previous animal studies have shown that the presence of paracetamol,
during the critical period of brain development in mice induced long-lasting
effects on cognitive function (Philippot, Gordh, Fredriksson, & Viberg, 2017;
Viberg, Eriksson, Gordh, & Fredriksson, 2014). However, ibuprofen exposure
during brain growth spurt did not affect brain development in mice (Philippot,
Nyberg, Gordh, Fredriksson, & Viberg, 2016; Philippot et al., 2017). In humans, a
recent review of prenatal paracetamol exposure and later neurodevelopmental
development showed an increased risk of adverse neurodevelopmental outcome.
The association was shown between foetal paracetamol exposure and increased
risk for later ADHD and hyperactivity. The problems with these studies are the
heterogeneity of the protocols and in their outcomes, and therefore the difficulty
to prove causality exists. Paracetamol, which is considered a safe medication for
pain and fever during pregnancy, is the most commonly used medication in
pregnancy (Werler, Mitchell, Hernandez-Diaz, & Honein, 2005). As it is also
widely used in term and preterm infants (Allegaert & van den Anker, 2017),
further research on its safety is urgently needed.
2.7 Association of the treatments of PDA with neonatal morbidities
It is unclear which is worse: the prolonged left-to-right shunt through PDA that
causes circulatory changes or the side effects of the therapies. The strength of the
side effects of NSAIDs medications must be weighed against very rapid surgical
40
ductal closure and its consequences on the circulation of very preterm
hemodynamically labile and fragile infants (Abdel-Hady, Nasef, Shabaan, & Nour,
2013; Evans & Iyer, 1994; Evans, 2015; Gudmundsdottir et al., 2015; Noori,
2010). The problems of these cause-consequences associations are even more
challenging in extremely premature infants, as later morbidities may simply be
consequences of prematurity itself (Laughon, Simmons, & Bose, 2004).
2.7.1 Associations with bronchopulmonary dysplasia (BPD)
The pathophysiology of BPD is multifactorial. The independent role of PDA and
the causality of its treatments with the risk of BPD is unclear. Previous studies
have suggested that PDA can contribute to the development of BPD by increasing
the fluid filtration to the lungs, thus causing pulmonary oedema and an increased
need for ventilator support (Noori, 2010). A former epidemiological study of
VLGA infants found a slight increase in the odds of BPD in infants with PDA
(Marshall et al., 1999). However, some studies show an association between
severe BPD and treatments for PDA. EPICE, a large European population-based
study (n=6896), indicated that preterm infants (born under 31 weeks) who had
treatment for PDA were at higher risk of BPD or death in all regions around
Europe, with an adjusted RR 1.33 (95% CI 1.18−1.51), than those who were not
treated. Survival without major neonatal morbidity was not related to PDA
treatment, demonstrating that variations in PDA treatments did not explain the
result. The incidence of BPD in 23− to 26-week gestational age infants was lower
in cases of expectant management for PDA than when PDA was treated with
either indomethacin or ligation (Sung et al., 2016). However, in the Trial of
Indomethacin Prophylaxis in Preterms (TIPP) study, the risk of BPD in infants
treated with prophylactic indomethacin was similar when compared to placebo.
Furthermore, in the TIPP study, the incidence of BPD was higher after
prophylactic indomethacin than after placebo treatment in infants without PDA
(Schmidt et al., 2006). Indomethacin implicates oliguria and fluid retention,
potentially predisposing premature infants to lung oedema. This side effect must
be considered when giving NSAID medications to very preterm infants. It has
been shown that sole fluid restriction has no effect in reducing BPD but does have
an effect in reducing PDA. In a systematic review comparing restricted fluid
intake and liberal fluid intake, less fluid was associated with reduction in PDA,
but there was only a trend towards a lower risk of BPD, RR 0.85 (0.63−1.14) (E.
F. Bell & Acarregui, 2008). Surgical ligation (prophylactic, primary, or secondary)
41
was also associated with an elevated risk of BPD (R. Clyman, Cassady, Kirklin,
Collins, & Philips, 2009; R. I. Clyman, 2013). In summary, active closure of PDA
has not been shown to reduce the risk of BPD, indicating an unclear association
the shunt of PDA and the risk of BPD.
2.7.2 Associations with other neonatal outcomes and mortality
COX-inhibitors have acute side effects, such as oliguria and risk of
gastrointestinal perforation that are described in greater detail in section 2.4.3.
Associations between the treatment of PDA and later neonatal morbidity have
been described. An association has been suggested between ibuprofen and
indomethacin and neonatal morbidities like ROP, NEC, and BPD (R. I. Clyman &
Chorne, 2007; Irmesi, Marcialis, Anker, & Fanos, 2014). An association between
surgical ligation and later neurodevelopmental impairment has been described
(Ibrahim et al., 2015; Sadeck et al., 2014). Surgical ligation after indomethacin
therapy has also been associated with NEC when compared to a conservative
approach (Jhaveri et al., 2010). However, the potential for ELGA infants to
succumb directly because of PDA or its treatments is rare (Patel et al., 2015).
42
43
3 Aims of the research Patent ductus arteriosus in preterm infants is one of the very important problems
in neonatal medicine. There are differences in both the definition and the
treatment strategies of hsPDA. COX-inhibitors and the ligation of PDA are
established therapies. In this thesis, we wanted to determine whether paracetamol
has the potential to become a novel treatment for PDA. After observational
studies on the association between paracetamol treatment and the incidence of
PDA, we attempted to explore whether paracetamol treatment for pain has a
biological effect on PDA. The currently available medical therapies and surgical
ligation have side effects in premature infants. We aimed to consolidate and
extend these observations using a national cohort of very preterm infants.
The specific aims of the research were:
– To study, in a retrospective trial, whether the introduction of paracetamol for
the treatment of pain in VLGA infants with respiratory distress would
influence the incidence of PDA (Study I).
– To study in a prospective randomised trial (RCT), whether paracetamol has a
biological effect on the early constriction of open DA in premature infants
(Study II).
– To study the adverse effects of paracetamol used in the early treatment of
preterm infants (II).
– To study the predisposing factors for PDA in VLGA infants in a national
cohort (Study III).
– To study the adverse effects of the therapies used for PDA closure in a large
epidemiological study during the first hospitalisation (Studies III and IV)
– To study the mortality of ELGA infants during the first hospitalisation period
and its possible associations to PDA (Study IV).
44
45
4 Patients and methods
4.1.1 Paracetamol for patent ductus arteriosus (I and II)
Study I
This retrospective study consists of 105 VLGA infants and 96 VLGA control
infants born before 32 gestation weeks admitted to the Oulu University Hospital
neonatal intensive care unit (NICU). The paracetamol group infants were born
between June 2009 and December 2011, and controls were born from January
2008 to May 2009. Infants with lethal malformations, chromosomal defects, or
severe congenital infections were excluded. Paracetamol was introduced
originally for VLGA infants’ mild and moderate pain in June 2009. Intravenous
(IV) paracetamol was given to infants before 72 h of age (Perfalgan® 10 mg/ml
solution for infusion, Bristol-Myers Squibb Finland, Espoo, Finland) The first
loading dose of paracetamol was 20 mg/kg, followed by 7.5 mg/kg maintenance
dose every 6 h. Paracetamol was given if there were clinical signs of pain, which
were systematically screened with the neonatal infant acute pain assessment scale
(NIAPAS). If the patient did not improve after starting paracetamol, IV morphine
was available. Paracetamol was stopped when no signs of pain were observed
during 24 h.
Heart echo was performed on postnatal days two to five. PDA criteria
included a significant left-to-right shunt with signs of hemodynamic distress (left-
atrium-to-aorta ratio >1.30, tachycardia or high pulse pressure) and persistent
respiratory distress. The size of PDA was measured as internal ductal calibre vs
pulmonary artery main branch root calibre. PDA was treated with a general
course of IV ibuprofen (10 mg/kg/day, then twice 5 mg/kg/day) which was
repeated once if necessary. Surgical closure of PDA was performed when
ibuprofen was not effective or was contraindicated. The closure of PDA was
determined by cardiac ultrasound. Moderate to severe BPD was diagnosed at 36
weeks of gestation using the oxygen weaning test, IVH was defined based on the
international schedule of Papile with several ultrasound exams, and NEC grade 2
to 3 was defined as described by Bell (M. J. Bell et al., 1978; Papile, Burstein,
Burstein, & Koffler, 1978; Walsh et al., 2004). Accurately recorded data on
paracetamol dosages, ibuprofen, surgical ligation, and known side effects of
paracetamol were obtained from the NICU patient database, Centricity Critical
46
Care Clinisoft (GE Healthcare Finland, Helsinki, Finland). These data were
reviewed with Crystal Reports XI software (SAP Finland Oy, Espoo, Finland).
Permission to use the hospital databases was given by the administrative chief of
Oulu University Hospital. Statistical analyses were performed using the PASW
Statistics 18 (SPSS Inc., Chicago, IL, USA). Continuous variables were analysed
using the independent samples t-test and dichotomous variables using the two-
tailed Chi-squared test. A multivariate analysis of factors influencing the risk of
PDA was performed by logistic regression. Significance was set at p<0.05.
Study II
This study was a randomised, double-blinded, phase I−II trial (The Premature
Infants’ Paracetamol Study, PreParaS study) with the aim of establishing a new
paracetamol indication in high-risk preterm infants The study group consisted of
VLGA infants (born < 32 gestational weeks) born in the Oulu University Hospital
NICU between September 18, 2013 and January 2, 2015. Infants requiring
intensive care were randomly assigned to the IV paracetamol or the placebo (0.45%
NaCl) group (Figure 3). The study was performed in accordance with Good
Clinical Practice guidelines. The hospital ethics committee and the Finnish
Medicines Agency (Fimea) approved the protocol. The monitoring officer
oversaw the trial arrangements regularly. This trial was assigned to the European
Clinical Trials Database (EudraCT 2013-008142-33) and the ClinicalTrials.gov
registry (NCT01938261).
47
Fig. 3. Recruitment flow chart in PreParaS study.
Randomisation and intervention
Infants were randomised to either the IV paracetamol or the placebo group (IV
0.45% NaCl). Computed randomisation was done using a 4-block design. To
decrease the risk of significant heterogeneity between cases and controls,
individual treatment strata were defined by gender and immaturity. All staff
(nurses and doctors treating patients) were blinded to the study medication. The
dose of paracetamol used for pain in neonates, included a first loading dose of 20
mg/kg, followed by 7.5 mg/kg every 6 h for 4 days, given in 15-minute infusions.
48
The study drug was started before 24 hours of age. No other paracetamol was
given before, during, or 2 days after (washout period) the study protocol.
Cardiac ultrasound (ECHO)
The first cardiac ultrasound was performed after recruitment but before the study
drug was started. After the study drug was administrated, ECHO was performed
daily until one day after the study medication was finished. Thereafter, in infants
with open DA, cardiac ultrasound to measure ductus calibre was performed once
or twice a week. All infants were examined at the time of discharge from NICU.
The ECHO was performed by neonatologists (n=3) who were trained by
paediatric cardiologist to enhance the uniformity of evaluations. Altogether, 330
ultrasound examinations were performed to study the infants. An interrater
reliability analysis for the 3 raters was calculated using the Cronbach’s α statistic
to determine consistency among raters. Patients were examined in the supine
position with slight left shoulder recumbences. The recordings were obtained
using Vivid i® (first eight patients) or Vivid S5® (GE Healthcare, Helsinki,
Finland) ultrasound devices with appropriate transducers (12S or 6S). No sedation
was used during the ECHO examinations. In cases where the infant was
distressed, the neonatal nurse soothed the infant, and oral 20% glucose solution
drops were administered if needed. ECHO parameters defined were ductal
internal calibre (mm) from the narrowest point of the duct from the pulmonary
side of the vessel and the left-atrium-to-aorta ratio (LA/Ao) from M-mode. The
smallest diameter of the ductal pulmonary end was measured from the
parasagittal plane of the high left parasternal window (ductal view). Diagnostic
criteria of hsPDA were internal ductal diameter > 50% wider than the left
pulmonary artery, LA/Ao ratio >1.4, and flow patterns showing a large left-to-
right ductal flow shunt.
Outcomes and statistics
The primary outcome was the decrease and closure of the ductus during the
intervention as a function of postnatal age. The secondary outcomes were: LA/Ao
ratio, the age of permanent closure of the ductus, treatment for ductus, the side
effects of paracetamol, neonatal morbidity, and mortality. Paracetamol
concentrations were analysed from serum samples stored at -70 C using the
Paracetamol Assay Kit. All samples were analysed as duplicates. The inter- and
49
intra-assay coefficients of variation were 18.1% and 14.1%, respectively.
Paracetamol concentrations were stable after prolonged storage.
Adverse effects such as low blood pressure and need of inotropes and laboratory
values like platelets, serum sodium, and bilirubin were recorded. Renal function
was monitored from urinary output (mL/kg/hour). Clinical symptoms of hsPDA
were murmur, prolonged ventilation, increased pulse pressure, cardiomegaly,
active precordium and bounding pulses. If PDA required closure, the decision was
made by a clinician. Options for treatment were ibuprofen and surgical closure.
Statistical analysis of Study II
Sample size assumed a 40% proportional difference between groups. It was
assumed that the ductus calibre would diminish during the study medication
period in 50% of the paracetamol-treated infants and 10% of the controls. In
power 80%, alpha-error 0.05 sample size was calculated to be 48 patients.
Outcomes were analysed as the intention to treat. The Mann-Whitney U-test or
the samples t-test was used for continuous variables and the Chi-squared test for
categorical values. Ductal closure postnatal ages were estimated using the
Kaplan-Meier analysis and the hazard ratios were calculated using the Cox
regression analysis. RANOVA (repeated measures analysis of variance) was used
to assess the daily variation in ductal fluid balance between the groups. Statistical
analysis was performed using IBM SPSS version 22.0 for Microsoft Windows
(IBM Acguires SPSS Inc., Chicago, IL, USA).
4.1.2 Morbidities and mortality associated with PDA treatments (III)
The study data were based on the Finnish Medical Birth Register of preterm
infants born before 32 gestational weeks (22−31). Data consisted originally of
4,143 VLGA infants born during the years 2005−2013 (Figure 4). Exclusion
criteria were lethal congenital malformation, lethal chromosomal defect, or death
before 7 days of postnatal age.
50
Fig. 4. Flow chart of population-based data
PDA treatments, morbidities and mortality, and other risk factors were recorded
from birth until discharge, or until the age of 42+0 postconceptional weeks. The
final study population consisted of 3,668 infants (Figure 4). Diagnosis of hsPDA
was based on the same clinical and echocardiographic criteria mentioned in the
methods for Study I and Study II. The definition of small for gestational age
(SGA) was based on reference values for normal growth in premature infants in
the Finnish population (Sankilampi, Hannila, Saari, Gissler, & Dunkel, 2013).
The duration of gestation was evaluated by ultrasound examination at an
estimated 16 weeks of gestation. The diagnosis of ROP was based on
international guidelines (International Committee for the Classification of
Retinopathy of Prematurity, 2005), and NEC was diagnosed on the basis of Bell
criteria (M. J. Bell et al., 1978), stages II and III being recorded. IVH grades were
defined as described by Papile (Papile et al., 1978). Severe IVH was defined as
51
being stage 3 or 4. Mild BPD (grade 1) was diagnosed based on the need for
supplementary oxygen or assisted ventilation at 28 postnatal days. If the infant
required less than 30% of supplementary oxygen at 36 weeks of gestation (±6
days), the oxygen reduction test was performed to define grade 2 (moderate) BPD
(Walsh et al., 2004). Severe BPD (grade 3) was diagnosed if the infant required at
least 30% oxygen or assisted ventilation to reach a saturation level of 90–96% at
the age of 36 gestational weeks (±6 days). Due to incomplete data for grade 2
BPD, only severe BPD (grade 3) was included in the final analysis (Table 3).
Inotrope use was recorded if IV inotropic agents (dopamine, dobutamine, and/or
noradrenaline) were administered. Respiratory support was defined in case of
either invasive ventilation (conventional or high-frequency oscillatory ventilation
[HFOV]) or non-invasive ventilation, which were recorded. Non-invasive
ventilation was recorded when nasal continuous positive airway pressure or a
high-flow nasal cannula was needed. All mortalities during the first
hospitalization were recorded up to postconceptional age 42+0 weeks.
Statistical analysis of Study III
A logistic regression analysis, with and without adjustment for gestational age at
birth (weeks), intrauterine growth (SGA), delivery hospital, and antenatal steroids,
was performed to evaluate the effect of early neonatal morbidity (RDS, need for
inotropes, surfactant therapy or mechanical ventilation) on the risk of PDA
requiring treatment. Multivariate logistic regression, with a forward stepwise
variable selection procedure was used to identify the most effective set of
predictors of early neonatal morbidity. A prior multivariate analysis of the
multicollinearity of the predictors used in the univariate analysis was performed
using a variation inflation factor (VIF). If the VIF of a given predictor was greater
than 3, that predictor was eliminated from the multivariate analysis. A logistic
regression analysis was also performed to evaluate the associations between the
treatments for the closure of PDA and serious morbidities, including severe BPD
(grade 3), ROP grades 3–5, NEC stages 2–3, IVH grades 3–4 and death. These
morbidities were adjusted with respect to antenatal factors (gestational weeks,
SGA, delivery hospital and antenatal steroids) and postnatal factor RDS. In
addition, a logistic regression analysis was performed to compare the risk of
severe IVH in the case of early (< 7 days) and late ligation. The results of the
logistic regression analyses were expressed as odds ratios (ORs), and their 95%
confidence intervals (95% CIs). The differences in mean birth weight and
52
gestational age between the treatment groups were tested with the Student’s t-test,
and differences among more than two groups were evaluated using an analysis of
variance (ANOVA), with Tukey’s HSD correction method for post hoc
comparisons. Differences in gender distribution were tested by the Chi-square test.
All the statistical analyses were performed with IBM SPSS Statistics for
Windows, (Version 22.0, IBM Corp, Armonk, NY).
4.1.3 National survival analysis of infants born extremely preterm (IV).
The study data were based on the Finnish Medical Birth Register of preterm
infants born 2005−2013 before 28 gestation weeks (22+5 ─ 27+6) without
congenital anomalies. The primary aim of the study was to define the mortality
risks of the most premature infants during the first hospitalisation period. The
original data consisted of 1,371 ELGA infants (born < 28 gestational weeks). Those
infants with lethal malformations or genetic defects were excluded.
Statistical analysis of Study IV
Differences in gender distribution were tested by the Chi square test. The
differences in mean birth weight and gestational age were tested with the
Student’s t-test. Mann-Whitney U-test was used to compare medians of skewed
distributed continuous variables, like postnatal age of death. Standardized Normal
Deviate (SND) test was used to compare the differences in the proportions of
neonatal morbidities and mortality between SGA and non-SGA infants.
Associations of neonatal morbidities with mortality were evaluated using logistic
regression analysis adjusted with antenatal steroids, gestational age at birth and
delivery hospital. Analyses were performed separately on SGA and non-SGA
infants. The results of the logistic regression analyses were expressed as odds
ratios (ORs) with 95% confidence intervals (95% CIs). Postnatal age of demise
was evaluated by Kaplan-Meier survival analysis and differences between non-
SGA and SGA infants were tested using Log-Rank test. All the statistical analyses
were performed with IBM SPSS Statistics for Windows, (Version 25.0, IBM Corp,
Armonk, NY).
53
5 Results
5.1 Paracetamol for patent ductus arteriosus
Study I
This retrospective study showed that the annual incidence of PDA decreased from
30.7% to 14.7% (p=0.008) after the introduction of paracetamol originally given
for pain management to VLGA infants in the NICU. After paracetamol
administration, there was less medical intervention for PDA (ibuprofen treatment
to 15 paracetamol group infants and to 26 controls, p=0.013). Three paracetamol-
exposed and 7 control infants required surgery (Table 3). No adverse events were
seen. Paracetamol treatment was associated with a lower relative risk for PDA
(RR 0.48, p=0.008, Chi-square) and a lower risk for ibuprofen therapy (RR 0.50,
p=0.013). Rate of PDA closure by ibuprofen was similar in males and females (81%
vs 73%).
54
Table 3. Characteristics of the groups
Characteristics Paracetamol group
n=102
Control group
n=88
p-value
Birth weight, g (SD) 1201 (379) 1308 (369) 0.051
Gestation weeks (SD) 28.5 (1.9) 29.0 (2.1) 0.09
Surfactant doses (SD) 1.1 (0.9) 0.9 (0.9) 0.21
Ventilation days (SD) 3.3 (7.1) 3.8 (9.4) 0.68
PDA diagnosis, n (%) 15 (14.7) 27 /30.7) 0.008
Ibuprofen treatment, n(%) 15 (14.7) 26 (29.5) 0.013
Surgical ligation, n (%) 3 (2.9) 7 (8.0) 0.12
Ductal closure (postnatal
day)
11 (20) 15 (41) 0.43
Highest bilirubin, umol/l, (SD) 150 (24) 159 (23) 0.018
NEC, n (%) 0 1 (1.1) 0.28
IVH gr 3-4, n (%) 4 (3.9) 2 (2.3) 0.52
BPD, gr 2-3 n (%) 11 (10.8) 5 (5.7) 0.21
The number of paracetamol doses per patient (mean, SD) was 17 (11.8). The
postnatal age (hours, SD) for the first dose was 13.2 (13.7), and the mean duration
of paracetamol (days, SD) therapy was 4.3 (3.1), showing that paracetamol
therapy was begun as a prophylactic drug very early in postnatal life. Short
duration of pregnancy decreased (OR 0.58, 95%CI 0.47−0.71), p<0.001), and
paracetamol increased the odds (OR 4.2, 95%CI 1.8−9.7, p=0.001) of closure of
PDA.
Study II
This randomised, controlled, and double-blinded study protocol showed for the
first time that paracetamol has a biological effect on PDA in very premature
infants soon after birth. The DA closed earlier in the paracetamol group than in
the control group infants (Figure 5). The protocol of serial cardiac ultrasound
examinations (n=330) was performed to all study infants. Interrater reliability (3
examiners) was alpha 0.97 (95%CI 0.90−0.99). Baseline characteristics were
similar in both groups (Table 4).
55
Table 4. Baseline characteristics of the PreParaS study
Characteristics Paracetamol group (n=23) Placebo group (n=25)
Gestational weeks, wk (SD) 28.4 (2.4) 28.3 (2.1)
Birth weight, kg, mean (SD) 1.22 (0.4) 1.12 (0.3)
Antenatal steroids, n (%) 20 (87) 25 (100)
Antenatal steroids, doses/mother,
mean (SD)
1.65 (0.9) 1.64 (0.5)
PROM, n (%) 10 (43) 6 (24)
Caesarean section, n (%) 15 (65) 10 (40)
Males (%) 13 (57) 14 (56)
Apgar at 5 min age, median (range) 7 (4-10) 6 (2-9)
Surfactant, n (%) 16 (70) 22 (88)
Surfactant doses per patient, mean (SD) 1.3 (1.3) 1.4 (0.9)
There was no difference in the basic (first measurement) ductal size between
groups. The mean (SD) first calibre of internal ductal diameter was 1.57 (0.7) mm
in the paracetamol group and 1.4 (0.8) mm in the placebo group (P=0.38). In the
paracetamol group, the ductus closed faster at the end of the intervention as
compared to the placebo (0.45% NaCl) group. The number of infants with a
closed DA was higher in the paracetamol group than in the placebo group (HR
0.49, 95% CI 0.25−0.97, P=0.016. The median (IQR) postnatal age (hours) for the
observed ductal closure in the paracetamol group was 41 (33−85), and in the
placebo group 78 (50−375), p=0.045. No difference was seen between the LA/Ao
ratios (p= 0.31). None of the infants had PDA treatments during the study drug
administration. Seven infants (14.6%) had therapy for PDA before their discharge
from the NICU. The mean (SD) postnatal age (hours) for ductal closure in infants
born after 27 weeks of gestation was 80 (151) in the paracetamol group vs 322
(514) in the placebo group (p=0.004). In the extremely preterm infants group
(born < 27 gestational weeks) (n=8), the effect of paracetamol for ductal closure
was not seen (p=0.63). Four (50%) of those infants had therapy for PDA (3 in
paracetamol group and 1 in placebo group).
56
Fig. 5. Percentage of infants with open ductus in function of postnatal age (hours) in paracetamol and placebo groups.
Paracetamol was well tolerated, and no acute side effects were seen. Secondary
outcomes are listed in Table 5. There was no difference in adverse events nor in
neonatal outcomes between the groups. Renal side effects were also not observed.
The urinary output during the first week of life was similar (p=0.102), and no
difference was seen in oliguria (urine output < 1 ml/kg/h) or polyuria (urine
output > 5 ml/kg/h). There was no difference between the groups regarding
phototherapy periods and highest bilirubin levels. Furthermore, no signs of
paracetamol-induced hypotension were seen as the requirement of inotropes were
similar (p=0.74).
57
Table 5. Secondary outcomes of the PreParaS study
Characteristics Paracetamol group
N=23
Placebo group
N=25
Treatment for PDA, n (%) 4 (17) 3 (12)
Mechanical ventilation,
d median (range)
1 (0-32) 2 (0-39)
Supplemental oxygen, d mean (SD) 20 (24.5) 22.4 (25.0)
Inotropes, n=0/1/2/31 17/7/0/1 16/5/0/3
Hypernatremia (>150 mmol/L), n (%) 5 (22) 12 (48)
Phototherapy periods, n mean (SD) 3.5 (1.7) 3.9 (2.0)
Highest s-bil, µmol/L, mean (SD) 159 (21) 158 (19)
BPD, gr 2-3 0 1 (4)
IVH gr 1-2, n (%) 5 (22) 9 (36)
Severe IVH, gr 3-4 1 (4) 1 (4)
NEC, grade 3, n (%) 0 1 (4)
ROP treated, n (%) 1 (4) 0
Death, n (%) 0 1 (4) 1=inotropes: 0=none, 1=dopamine/dobutamine, 2=dopamine and dobutamine, 3=dopamine, dobutamine
and norepinephrine
Paracetamol concentrations were analysed in serum samples (n=87). No toxic
level was noticed in paracetamol concentrations (range 0−25.2 mg/L), and no
accumulation of drug level was seen during the drug administration period. Mean
(SD) concentration during day one was 9.8 (5.5) mg/L (n=26), and the same on
day four of the drug administration was 11.8 (6.0) mg/L (n=17, P=0.29). No
gender difference was seen in paracetamol levels (boys’ mean (SD) concentration
was 9.2 (6.2), while girls’ mean was 9.0 (5.6) mg/L) (p=0.91). When the most
immature infants were analysed further, those born < 29 gestational weeks did not
differ in their concentrations from those born > 29 gestational weeks (9.4 (5.5) vs
8.9 (6.2) mg/L, respectively, P=0.71. In conclusion, paracetamol concentrations
did not explain the differences in ductal closures.
5.2 Morbidities and mortality associated with PDA treatments (III)
Original cohort data consisted of 4,143 VLGA infants born in Finland during
2005−2013. Most of the infants (91%) were born in university hospitals, and only
9% were born at local or central hospitals. After exclusion, the final data
consisted of 3,668 VLGA infants whose mean gestational age was 29.1 weeks,
and the mean birth weight was 1243 g (Table 6). PDA treatment had been
58
administered to 30.9% of the infants, and of those, the majority (90.1%) had
received medical treatment for the closure of PDA. Surgical ligation was
performed in 9.9% (362/3668) of the infants. Surgery was the primary treatment
in 112 cases, and 250 infants had both medical and surgical treatment (Table 6).
In ELGA infants (< 28 weeks), the rate of PDA treatment was three times higher
than among infants born at 28 weeks or later (i.e, 619 of 1060 cases required
therapy for PDA; 58.4% vs 19.7%).
59
Table 6. Final study population and treatments of PDA.
Characteristics No therapy
n=2536
Medical
N=770
Direct
Ligation
N=112
Both
therapies
N=250
Total
N=3668
Gestational age, week, mean
(SD)
29.7 (1.9) 28.3 (2.1) 26.1 (1.9) 26.1 (1.9) 29.1 (2.2)
Birth weight, kg, mean (SD) 1340 (371) 1115 (336) 834 (297) 846 (278) 1243 (390)
SGA, n (%) 350 (13.8) 111 (14.4) 20 (17.9) 27 (10.8) 508 (13.8)
Antenatal steroids, n (%) 2368 (94.9) 719 (94.5) 100 (90.1) 242 (98) 3429 (94.9)
Apgar at 5 min, md1 (range) 8 (6-9) 7 (6-8) 6 (5-7) 6 (5-7) 7 (6-8)
Intubation, n (%) 917 (37.9) 421 (55.5) 105 (95.5) 189 (75.9) 1632 (46.2)
RDS, n (%) 1394 (55.0) 671 (87.1) 108 (96.4) 239 (95.6) 2412 (65.8)
Surfactant therapy 1232 (48.6) 632 (82.1) 102 (91.1) 233 (93.2) 2199 (60.0)
Conventional ventilation,
n(%)
1359 (53.6) 658 (85.5) 111 (99.1) 246 (98.4) 2374 (64.7)
HFOV, n (%) 215 (8.5) 145 (18.8) 75 (67.0) 116 (46.4) 551 (15.0)
Postnatal steroids, n (%) 186 (7.3) 121 (15.7) 69 (61.6) 104 (41.6) 480 (13.1)
1=median
Postnatal age of the PDA treatments was analysed for different treatment groups.
The mean postnatal age (SD) for the first dose of medical treatment was 4.0 (4.1)
days, and that of primary surgical ligation was 13.8 (11.4). Of those who had
medical treatment followed by surgery, the former was at a mean age of 4.1 (4.7)
days of life, and the latter was at 15.7 (12.0). The infants who responded to
medical treatment were born later in gestation (mean of 28.3; difference of means
of 2.1; 95% CI 1.8–2.4; P<0.001) and had a higher birth weight (mean of 1115 g;
difference of means of 336; 95% CI: 227–311; P<0.001) than the nonresponders.
Those infants who underwent primary surgical ligation had a mean gestational
age of 26.2 weeks (SD 1.9) and a mean birth weight of 834 g (SD 297). However,
the infants who did not have PDA therapy had a longer gestation age (29.7 weeks,
SD 1.9) and a higher birth weight (1340 g, SD 371) than those that required
treatment for PDA (P<0.001 for all three post hoc comparisons). No gender
differences were found with regard to the PDA therapies (P=0.212).
Study III stated that RDS and the need for mechanical ventilation were
independently associated with the risk of PDA requiring therapy. The severity of
lung disease, rather than prematurity per se, was associated with the risk of
hsPDA. After adjustment (for gestational weeks, growth restriction, and hospital
of birth), odds were to RDS (OR 1.9 95%CI 1.0–3.5, p=0.042) and mechanical
ventilation (OR 2.0 95%CI 1.1–3.6, p=0.030). In ventilated infants, however, the
60
ventilation mode HFOV was independently associated with a decreased risk of
PDA after controlling other variables in the model.
The population-based cohort study of VLGA infants also showed that
medical and surgical treatment of PDA was associated with the risk of severe
BPD (OR: 2.1; 95% CI: 1.4−3.0, P<0.001; and OR: 4.0; 95% CI: 2.0–8.2,
P<0.001, respectively). The association was strongest in ELGA infants who
required both medical treatment and surgical closure of PDA (OR: 8.2; 95% CI:
3.5–19.1; P<0.001). Primary surgical ligation additionally increased the risk of
both severe IVH (OR: 4.3; 95% CI: 2.5–7.3; P<0.001) and grade 2-3 NEC (OR:
2.1; 95% CI: 1.2–3.6); P<0.007). However, medical treatment was associated
with lower mortality. Severe ROP (grades 3−5) was not associated significantly
with any treatment for PDA. In conclusion both medical and surgical therapies for
PDA were associated with severe BPD, and primary surgical ligation was
associated with NEC and severe IVH. Furthermore, ligation during the first week
of life was associated with a remarkably increased risk of severe IVH relative to
later ligation (OR: 4.9; 95% CI: 2.5–9.8; P<0.001). Medical treatment itself and
followed by surgery was associated with lower mortality after adjusting for
gestational age, intrauterine growth restriction (SGA), delivery hospital, and
antenatal steroids.
Table 7 shows the associations of PDA treatments with neonatal morbidity
and mortality during the first hospitalisation period. Different treatment groups
are compared to infants with no treatment for PDA, and associations are shown as
odds ratios (ORs) and their 95% confidence intervals (95% CIs). These results are
adjusted for gestational weeks, SGA, delivery hospital, antenatal steroids, and
RDS.
61
Table 7. VLGA infants’ neonatal morbidity and mortality ORs in different PDA treatment groups (compared to no PDA treatment).
All <28 gestation weeks
Outcome/ treatment OR 95% CI P-value OR 95% CI P-value
Severe ROP
Medical 1.1 (0.5-2.4) 0.797 0.9 (0.4-2.1) 0.752
Ligation 0.6 (0.1-2.9) 0.532 0.3 (0.04-0.2) 0.231
Both therapies 1.5 (0.6-4.0) 0.399 1.5 (0.6-4.1) 0.388
Severe BPD
Medical 2.1 (1.4-3.0) <0.001 2.3 (1.3-4.1) 0.007
Ligation 4.0 (2.0-8.2) <0.001 4.4 (2.0-9.7) <0.001
Both therapies 5.8 (3.1-11.1) <0.001 8.2 (3.5-9.1) <0.001
NEC gr 2-3
Medical 1.3 (0.9-1.8) 0.151 1.3 (0.8-2.1) 0.245
Ligation 2.1 (1.2-3.6) 0.007 2.2 (1.2-3.9) 0.010
Both therapies 1.4 (0.9-2.3) 0.176 1.4 (0.8-2.3) 0.278
Severe IVH
Medical 1.1 (0.7-1.6) 0.817 0.9 (0.5-1.5) 0.058
Ligation 4.3 (2.5-7.3) <0.001 4.4 (2.4-8.1) <0.001
Both therapies 1.3 (0.8-2.2) 0.311 1.2 (0.7-2.1) 0.601
Mortality
Medical 0.5 (0.3-0.9) 0.011 0.4 (0.2-0.8) 0.008
Ligation 1.0 (0.5-1.8) 0.901 0.9 (0.4-1.7) 0.649
Both therapies 0.3 (0.2-0.7) 0.003 0.3 (0.1-0.5) <0.001
5.3 Mortality of infants born extremely preterm (IV)
The mean gestational weeks (SD) of the data was 25.7 (1.6), and the mean birth
weight (SD) was 800 g (225) Treatment of PDA was administered to 47.6% of the
infants (644/1353). Surgical ligation was performed on 22.2% of the infants
(301/1353), and in those, the direct ligation proportion was 7.0%. Median
postnatal age (days) of death in non-SGA infants was 17.6 (range 307), and that in
SGA infants was 47.8 days (range 208), p=0.053. During the third day of life, the
SGA infants’ proportion for death began to differ from that of normal growth
infants, after that, the survival proportion was poorer in SGA infants through the
first hospitalization period (Figure 6). After adjustment for antenatal steroids,
gestational weeks and delivery hospital growth restriction was a clear independent
risk factor for mortality (OR: 4.6; 95% CI: 2.6–8.1; P<0.001).
62
Fig. 6. SGA and non-SGA survival curve during the first hospitalisation period
RDS [OR 2.3; 95% CI (1.0−5.2), P=0.040] and NEC were also associated with
higher mortality [OR 4.8; 95% CI (2.9−7.7), P<0.001]. Severe IVH was
associated with mortality in non-SGA infants [OR 3.4; 95% CI (1.9−6.0),
P<0.001], but not in SGA infants [OR 3.3; 95%CI (0.5−23.0), P=0.232]. When
studied further, diagnosis of pre-eclampsia was associated with the lower
incidence of severe IVH. Thereafter, maternal pre-eclampsia was associated with
lower mortality during the first week [OR 0.5; 95%CI (0.4−0.8), P=0.004], but
was not associated after one week of survival [OR 0.6; 95%CI (0.3−1.2),
P=0.178].
None of the treatments for PDA associated with the increased mortality of
ELGA infants after adjustment. However, medication therapy [OR 0.5; 95% CI
(0.3−0.99), P=0.045] and combination therapy [OR 0.3; 95% CI (0.1−0.6),
P=0.001] of PDA associated with lower risk of mortality. This association was not
seen in direct surgical ligation group [OR 1.1; 95% CI (0.6−2.2), P=0.736]. There
was clear difference in causes of death between SGA and non-SGA infants. SGA
63
infants succumbed to lung diseases (RDS, severe BPD), while NEC and severe
IVH were the major causes of death for normal-growth ELGA infants.
64
65
6 Discussion The decision to treat PDA in a very preterm infant should be based on
comprehensive clinical and echocardiographic markers of hsPDA. Adequate
diagnosis should be based on clinical symptoms in combination with ECHO
parameters. ECHO criteria of the diagnosis should be based on both the
magnitude of the left-to-right shunt and its individual impact on the patient’s
hemodynamic changes to define the optimal postnatal time for treatment.
Treatment should not harm the patient more than the disease (the open ductus)
itself. Current evidence does not support prophylactic indomethacin, ibuprofen or
surgical ligation. Premature closure of PDA has not been proven to affect later
outcomes, and the risks of side effects of the early treatments are higher when
compared to later treatment. It is important to avoid overdiagnosis and subsequent
overtreatment. However, the optimal anticipation in the treatments timing is
important, which mean diagnosis at the proper time and treating a
hemodynamically open ductus before hemodynamic collapse. In conservative
treatment, watchful waiting with fluid restriction is a good choice when ductal
flow does not harm the infant but the flow pattern and clinical symptoms require
therapeutic attention. Medical treatment is the primary choice, followed by
surgical ligation according to clinicians’ individual choice.
A retrospective study of paracetamol (I) discovered that the incidence of PDA
was apparently decreased with no adverse effects after introduction of
paracetamol for treatment of pain in VLGA infants. In the present RCT, the
infants were treated with a four-day course of paracetamol or placebo. We found
for the first time that paracetamol has a biological effect on the early constriction
of PDA in very preterm infants. Although the precise mechanism of paracetamol
is unclear, it inhibits the peroxidase moiety of the prostaglandin synthase enzyme,
thus decreasing the main ductal vasodilator PGE2 (with PGI2) levels.
Prostaglandin levels drop, and the DA contracts. According to present RCTs and
additional studies (Dang et al., 2013; El-Mashad et al., 2017; Oncel et al., 2014;
Yang, Gao, Ren, Wang, & Zhang, 2016), there is sufficient evidence to indicate
that paracetamol could be a new medication for closure of PDA in premature
infants. It has been shown to have the same effect as the NSAID drugs ibuprofen
and indomethacin, but with fewer acute side effects on the kidneys and the
gastrointestinal tract. This is because paracetamol does not cause generalised
vasoconstriction as do the COX-inhibitors ibuprofen and indomethacin (Gournay
et al., 2004).
66
The optimal time for therapeutic closure of PDA in very premature infants is
controversial. Premature closure with either medication or ligation has been
associated with adverse effects in several studies, although in theory it would be
an attractive approach. Study II indicated that very early administration of
paracetamol using the dosage effective for the treatment of pain did not result in
obvious adverse effects. In ELGA infants, however, no effect on the DA was
observed; these infants had neither benefits nor adverse effects. This raises some
questions about whether the dose or regimen should be different in the most
immature infants, those born under 28 weeks. Study II also showed that male
infants responded better to paracetamol than females, but possibly because of the
small sample size, this result was not statistically significant. The sample size of
Study II was able to prove evidence that paracetamol has an acute effect to PDA,
but it was not powered enough to show the effects in the subgroups. However, the
study’s findings on efficacy and safety were promising enough to indicate further
studies, including a large randomised trial.
The dose and course regimen for PDA closure are unclear, especially for the
most immature infants. The effect of paracetamol might be dose dependent, and
serum concentrations required for PDA closure might be higher than required for
the treatment of pain and antipyretics. Paracetamol is a safe drug when used in
regular doses, but there is still no evidence regarding adverse side effects, in the
long term. Therefore, it cannot be recommended as a first line-therapy for PDA.
The role of prolonged left-to-right shunt and its consequences for later
outcomes is controversial. There may be bias in studies comparing “standard”
treatments and conservative treatment because groups may differ in origin or
confounding factors (e.g, hospital differences) may make the cause-consequence
analyses difficult or even impossible. Prolonged open ductus is associated with
BPD, but so are the treatments (R. I. Clyman, 2013; Madan et al., 2009; Schmidt
et al., 2006; Terek, Yalaz, Ulger, Koroglu, & Kultursay, 2014). The possible role
of PDA in BPD aetiology is unclear. The precise time postnatally when the ductal
shunt changes from physiological to pathophysiological, thus causing higher
morbidity and mortality for premature infants, is also controversial. The
epidemiological study III showed that all therapies for PDA were associated with
severe BPD. The strongest association was seen in those infants who had surgical
ligation of PDA after failed medical therapy. Indomethacin has been implicated in
oliguria and fluid retention, potentially predisposing premature infants to lung
oedema (Schmidt et al., 2006). Surgical ligation (prophylactic, primary or
secondary) for PDA has shown to associate with an elevated risk of BPD (R.
67
Clyman et al., 2009; R. I. Clyman, 2013). There were 112 infants in Study III who
underwent direct ligation for PDA. Unfortunately, the reason for choosing direct
ligation was not identifiable in the data. Most of those infants were ELGA and the
association with severe IVH and ligation must be interpreted with caution, as the
order of these events is unclear. Severe IVH in very preterm infants mostly occur
during the first 3-4 days of life, and the risk is highest in ELGA infants (Szpecht,
Szymankiewicz, Nowak, & Gadzinowski, 2016). In some cases, the diagnosis of
severe IVH may be considered a contraindication to medical therapy of PDA.
However, as the risk of IVH was almost five-fold higher in infants with early
ligation compared to late ligation (> 7 days of life), the potential role of early
ligation in the development of IVH is worth considering. Surgical closure of PDA
may cause a rapid increase in cerebral perfusion. This in combination with the
fragile vasculature of the germinal matrix and potential reperfusion injury is
likely to predispose to bleeding. In the Study III surgical ligation was associated
with risk of NEC. This finding is in accordance with that of a previous study,
which found a significantly lower rate of NEC in ELGA infants treated by a
conservative approach in comparison to infants treated with early ligation
following indomethacin therapy (Jhaveri et al., 2010).
Although epidemiological studies III and IV were comprehensive, they have
several limitations. As with all register-based studies the cause-and-effect
relationships are difficult to verify and should be considered only as associations.
A range of hospital-driven, genetic and acquired factors may potentially influence
to the outcome. Due to the variability in diagnosing hemodynamically significant
PDA the diagnosis depends on both the centre and the individual clinician.
Although the results confirm and extend the associations between PDA and life-
threatening morbidities that have been obtained in other studies of smaller
populations, further prospective follow-up studies are needed.
In conclusion, these results show that ductal treatment should always be
based on a precise and comprehensive clinical (individual) evaluation of both of
the risk of the large ductal shunt and possible adverse consequences of hsPDA
treatments. Paracetamol may prove to be particularly suitable treatment for early
closure of ductus as it additionally appears to be safe. However, more prospective
trials are needed to show the optimal treatment, dosage, time, and associations of
the treatments for later outcomes.
68
69
7 Conclusions – The incidence of PDA decreased after the start of paracetamol administration
in the NICU.
– IV paracetamol had a favorable effect on DA contraction.
– No acute adverse effects of paracetamol were seen.
– Paracetamol is a potentially safe and effective drug that induced closure of
the DA in very preterm infants. At present, it cannot be recommended for
first-line therapy in treatment of PDA in premature infants. More prospective
studies are needed to determine before high-quality evidence of the dosage
and the long-term side effects.
– Conservative management (watchful waiting) is a valid therapy for PDA
when the open ductus does not harm the patient’s hemodynamic and organ
perfusion. Because of the possible side effects of routine therapies, premature
closure of the DA with currently available drugs, and in particular, routine
early ligation should be avoided.
– Both medical therapy and surgical ligation associated with later risk for
severe BPD.
– Direct ligation very early (before 7 days of life) is associated with severe IVH
and NEC.
– PDA treatments were not associated with higher mortality in ELGA infants.
70
71
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Original publications I Aikio O., Härkin P., Saarela T., & Hallman M. (2014). Early paracetamol treatment
associated with lowered risk of persistent ductus arteriosus in very preterm infants. J Matern Fetal Neonatal Med, 27(12), 1252-6.
II Härkin P., Härmä A., Aikio O., Valkama M., Leskinen M., Saarela T., & Hallman M. (2016). Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. J Pediatr. 177, 72-77.e2.
III Härkin P., Marttila R., Pokka T., Saarela T., & Hallman M. (2017) Morbidities associated with patent ductus arteriosus in preterm infants. Nationwide cohort study. J Matern Fetal Neonatal Med. 11, 1-8. doi: 10.1080/14767058.2017.1347921.
IV Härkin P., Marttila R., Pokka T., Saarela T., & Hallman M. (2018). National survival analysis of infants born extremely preterm. Manuscript.
Reprinted with permission from Taylor & Francis (I, III) and Elsevier Inc. (II)
Original publications are not included in the electronic version of the dissertation.
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CLOSURE OF PATENT DUCTUS ARTERIOSUS IN VERY PRETERM INFANTSPOTENTIAL ROLE OF PARACETAMOL AND CONSEQUENCES OF CURRENT TREATMENTS
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE:MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL