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ACTA BIOMEDICA

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Acta Biomed. - Vol. 86 - Suppl. 1 - June 2015 | ISSN 0392-4203

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Official Journal of the Society of Medicine and Natural Sciences of Parma

SUPPLEMENT

MEETING ON SUrfACTANT 2015 frOM ThE ELGA TO LATE PrETErM: whICh rESPIrATOry MANAGEMENT?Parma, Italy, June 18th 2015

00-cop suppl senza data.indd 1 10/06/15 10:21

Fernando Arevalo - Caracas, Venezuela Judy Aschner - Nashville, TN, USA Michael Aschner - Nashville, TN, USA Franco Aversa - Parma, ItalyAlberto Bacchi Modena - Parma, Italy Salvatore Bacciu - Parma, Italy Cesare Beghi - Varese, Italy Stefano Bettati - Parma, Italy Corrado Betterle - Padova, Italy Saverio Bettuzzi - Parma, Italy Mauro Bonanini - Parma, Italy Antonio Bonati - Parma, Italy Antonio Bonetti - Parma, Italy Loris Borghi - Parma, Italy David A. Bushinsky - Rochester, NY, USAOvidio Bussolati - Parma, ItalyArdeville Cabassi - Parma, Italy Paolo Caffarra - Parma, ItalyAnthony Capone Jr. - Detroit, MI, USA Francesco Ceccarelli - Parma, Italy Gian Paolo Ceda - Parma, Italy Graziano Ceresini - Parma, ItalyMarco Colonna - St. Louis, MO, USA Paolo Coruzzi - Parma, Italy Lucio Guido Maria Costa - Parma, ItalyCosimo Costantino - Parma, Italy

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Editor-in-Chief: M. VanelliPrinted in: June 2015Registrazione del Tribunale di Parma n° 253 del 21/7/1955

02-author guidelines.qxp_02-authors guidelines 10/06/15 10:23 Pagina 2

IndexVolume 86 / Supplement 1/2015

Meeting on Surfactant 2015From the ELGA to Late preterm: which respiratory management?

Parma, Italy, June 18rd 2015

5 Foreword

7 F. Rech Morassutti, I. Satariano, N. Doglioni, G. Criscioli, F. Cavallin, C. Gizzi, C. Martano, F. Ciralli, F. Torielli, P. E. Villani, S. Di Fabio, L. Quartulli, L. Giannini, D. Trevisanuto, on behalf of Neonatal Resuscitation Study Group,Italian Society of Neonatology

Delivery room management of ELBW infants in Italy

11 L. Capasso, J. Cerullo, L. Bucci, A. C. Borrelli, R. Caiazzo, F. Raimondi Respiratory management of ELGA infants in a region of Southern

Italy

16 H. Fuchs German experience in the management of ELGAN infants

21 E. Ferrazzi, D. Casati, S. Zullino, E. Rosti Obstetrical management of fetus with intra uterine growth restriction

(IUGR) and late IUGR

24 G. Lista, A. La Verde, F. Castoldi LISA: Surfactant administration in spontanous breathing. Which

evidence from the literature?

27 S. Mannarino, G. Corana, A.Zaroli, A.C. Codazzi, M. Pasotti, R.M. Cerbo, M.Stronati

Hemodynamic management of the preterm infant with acute respiratory failure: role of the functional echocardiography

32 S. Nobile, V.P. Carnielli Caffeine for preterm infants: current indications and uncertainties

36 L. A. Ramenghi Late preterm babies and the risk of neurological damage

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Acta Biomed 2015; Vol. 86, Supplement 1: 5 © Mattioli 1885

F o r e w o r d

This supplement of Acta Biomedica collects the Proceedings of the workshop “Dagli ELGA ai Late Preterm: quale approccio?”, held in Parma on 18-19 june 2015. The obstetrical assistance of pregnancies complicated by intrauterine growth restriction of foetus, the delivery room and NICU management of respiratory and cardiac failure, the modality of exogenous surfactant replacement by non invasive procedure (LISA) and the neurological outcome of very critical preterm babies, were the goals of our meeting with Italian and foreign speakers.

With the hope that this supplement can arouse your interest and above all support you in everyday clinical practice, we wish you all good reading.

Guest editors Giovanni Vento

Gianluca Lista

Delivery room management of ELBW infants in ItalyFrancesca Rech Morassutti1, Irene Satariano1, Nicoletta Doglioni1, Giulio Criscoli2, Francesco Cavallin3, Camilla Gizzi4, Claudio Martano5, Fabrizio Ciralli6, Flaminia Torielli7, Paolo E. Villani8, Sandra Di Fabio9, Lorenzo Quartulli10, Luigi Giannini11, Daniele Trevisanuto1, On Behalf of Neonatal Resuscitation Study Group, Italian Society of Neonatology1 Children and Women’s Health Department, Medical School University of Padua Azienda, Padua, Italy; 2 Italian Army - Signals and Information Technology HQ - C4 Systems Integration Development, Treviso, Italy; 3 Independent Statistician, Padua, Italy; 4 Neonatal Intensive Care Unit Pediatric, Neonatal Department ‘S.Giovanni Calibita’, Fatebenefratelli Hospital, Rome, Italy; 5 Neonatal Intensive Care Unit, Pediatric Department, Medical School University of Turin, Azienda Ospedaliera OIRM-S, Torino, Italy; 6 Neonatal Intensive Care Unit, Department of Mother and Infant Science Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 7 Neonatology Unit, University of Genova, Azienda Ospedaliera San Martino IRCCS – IST National Institute on Cancer Research, Genova, Italy; 8 Neonatal Intensive Care Unit, Maternal and Pediatric Department, Carlo Poma Hospital, Mantova, Italy; 9 Neonatal Intensive Care Unit, Department of Mother and Infant Science, ‘San Salvatore’ Hospital, L’Aquila, Italy; 10 Neonatology Unit, ‘A. Perrino’ Hospital, Brindisi, Italy; 11 Pediatric Department, Medical School University ‘La Sapienza’ Rome Azienda Ospedaliera Policlinico Umberto, Rome, Italy

Summary. In this article we evaluated the consistency of practice and the adherence to the International Guidelines in early delivery room management of ELBW infants in Italy. A polyethylene bag/wrap was used by 54 centres (55.1%). In Northern regions, one centre (2.5%) reported to use oxygen concentrations >40% to initiate positive pressure ventilation in ELBW infants. These proportions were higher in the Cen-tral (14.3%) and Southern (16.2%) areas. A T-piece device for positive pressure ventilation was widely used (77/97, 79.4%). A median of 13% (IQR: 5%–30%) of ELBW infants received chest compressions at birth in Italy. Forty-seven out of 98 (47.9%) centres declared to administer prophylactic surfactant in delivery room. Although there were geographic differences in the country, our results showed a good general adherence to the International Guidelines for Neonatal Resuscitation. (www.actabiomedica.it)

Key words: delivery room, ELBW, infants

Acta Biomed 2015; Vol. 86, Supplement 1: 7-10 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

Approximately 5 to 10% of newborns require some assistance to begin breathing at birth. About 3% are managed with positive pressure ventilation (PPV) and <1% require extensive resuscitative measures such as intubation, chest compressions and medication. These percentages rise noticeably in preterm infants (1-3). An increasing body of evidence suggests that deliv-ery room management of extremely low birth weight (ELBW) infants may have a direct influence on their survival and long-term morbidity (3-6). Therefore, their general outcome could be improved throughout a

structured and well-coded approach starting from the first minutes of life (7-10).

In this article we evaluated the consistency of practice and the adherence to the International Guide-lines for Neonatal Resuscitation in early delivery room management of ELBW infants in Italy.

Methods

The study was conducted between April and Au-gust 2012. A structured 73-item questionnaire and an accompanying introductory letter were sent by email

F. Rech Morasutti, I. Satariano, N. Doglioni, et al.8

to the directors of the 107 Italian level III centres who provide on-site delivery, based on the Italian Society of Neonatology database. Participation was entirely voluntary.

Statistics

Categorical data are expressed as numbers and percentages, continuous data as medians and inter-quartile ranges (IQR). Statistical analysis was per-formed using R 2.12 language (R Development Core Team 2010. R: A language and environment for sta-tistical computing. R Foundation for Statistical Com-puting, Vienna, Austria. ISBN 3-900051-07-0).

Results

A total response rate of 92% (98/107) was ob-tained. There was a homogeneous representation of the country: North 40/43 (93.0%); Centre 21/21(100%); South 37/43 (86.0%).

Characteristics of centres

Participating centres reported an overall number of 198.322 births during 2011, and of these, 1933 were ELBW infants. Northern and Central centres had a higher median of births and of ELBW infants than Southern centres.

A provider skilled in neonatal resuscitation was present in high-risk deliveries in 46% of the centres: this rate was higher in Northern (77.5%) than in Cen-tral (33.3%) and Southern (21.6%) centres.

Temperature management

The median delivery room temperature was 24°C (IQR: 22–25). Only 18 centres (20.2%) achieved a de-livery room temperature over 25°C. The use of a poly-ethylene bag for the management of ELBW infants at birth was reported by 54 centres (55.1%), with the highest rate in Northern ones (31/40, 77.5%). Fifty-nine centres (60.2%) used a cap to cover the head of the patients at birth.

Oxygen therapy

Only a limited number of centres (10/98, 10.2%) said they used oxygen concentrations >40% to initiate resuscitation. Of these 10 centres, five said they used a 100% oxygen concentration. Almost all of these centres belonged to the Central and Southern groups. Most cen-tres had a pulse oxymeter (91/98, 92.9%) available in de-livery room and used saturation targets (82/98, 83.7%).

Ventilatory support

Almost all centres used a facial mask as initial in-terface for PPV (95/98, 96.9%; the T-piece device was widely used (77/97, 79.4%). The use of positive end ex-piratory pressure (PEEP) during PPV was reported by 88 centres (89.8%). Continuous positive airway pressure (CPAP) was widely used to avoid intubation (85.4%). The oral route of intubation was chosen by most centres (61.2%), but there was a large difference in geographical subgroups. Northern centres preferred the nasal route (82.5%), whereas Central and Southern centres used the oral route (81.0% and 97.3%, respectively).

The percentage of ELBW infants intubated at birth had a median of 60% (IQR: 40%–80%), with the highest values in Central group (median 66%, IQR: 50%–75%). The percentage of ELBW infants receiv-ing only nasal-CPAP at birth had a median of 22% (IQR: 10%–40%), with the highest values in Northern group (median 25%, IQR: 8%–45%). The percentage of ELBW infants managed without any respiratory support at birth had a median of 3% (IQR: 0%–10%).

Chest compressions and medications

A median of 13% (IQR: 5%–30%) of ELBW in-fants received chest compressions at birth, mostly in Central (median 18%) and Southern (median 22%) centres.

Medication was given at birth to 6% of ELBW infants (IQR: 0–17%).

Surfactant therapy

In 47/98 (47,9%) centres surfactant was routinely administered in DR. The percentage of ELBW infants treated with INSURE at birth was 0% (0%-80%).

Delivery room management of ELBW infants in Italy 9

Discussion

This study reflects the early delivery room man-agement of ELBW infants in Italy. There were rel-evant differences among geographical areas in the ap-proach to the care of ELBW infants at birth.

As the delivery room management of ELBW infants may have a direct influence on the immedi-ate survival and also on long-term morbidity (3–6), the results of this study suggest that further efforts are needed to improve this area of care. Previous studies have reported important differences in mortality rates among neonatal units and geographical regions, irre-spective of the infant’s characteristics, suggesting vari-able degrees of effectiveness of medical care (11,12).

In the last version of the ILCOR Committee on Neonatal Resuscitation, the body of recommendations devoted to the management of ELBW infants has been progressively increasing (1). These include strate-gies to prevent thermal losses, oxygen administration and ventilation. Our data show a different adherence to the guidelines in relation to the geographical area with the highest rates in Northern regions and lowest in the Southern areas. For example, the implementa-tion of a simple practice to prevent hypothermia such as the use of polyethylene bag/wrap was limited to 37.8% of the centres in the South, in comparison with 77.5% in the Northern regions. A very similar picture was documented for other important interventions, such as the initial fraction of oxygen.

The reasons for such discordance could be due to different organizational and educational programs among the country’s regions. Although the role of continuous medical education is well-recognized, ef-fective training programs, benchmarking and qual-ity improvement initiatives should be further imple-mented and monitored. A national neonatal network including all level III Italian hospitals should be also sustained for continuous monitoring and comparison of short and long-term outcomes (13).

World Health Organization Guidelines, updated in 2003, state that environmental temperatures should be ≥25°C (14). Despite this guidance, delivery room temperatures are consistently reported to be lower than this in all healthcare settings (15,16). Also our study showed a low adherence to international guidelines

that does not appear to be influenced by geographical area. The reasons that impede a widespread adoption of higher environmental temperatures remain unex-plained, but perinatal teams have to consider this to be one of the greatest challenges in improving thermal care for newborn infants.

In addition, the percentages of ELBW infants who received chest compressions at birth were mark-edly different among the surveyed regions (median: North 5%; Centre 18%; South 22%). In the North American Vermont Oxford Network registry, which collected data on infants with birth weight of 501 to 1500 g, the proportion of those who received chest compressions was about 6% (17).

About half of the centres adopted a prophylactic strategy for surfactant administration. This approach disagree with the results of a recent meta-analysis showing a slight effect (survival without bronchopul-monary dysplasia at 36 weeks) in favor of early CPAP when compared to intubation at birth (18). However we don’t know if this approach has recently changed based on the results of the most recent randomized controlled trials on this subject (18).

Overall, the results of our study are very similar to those reported in a recent survey conducted in UK: the authors found many areas of good evidence-based delivery room practice, but they identified also signifi-cant variation in delivery room resuscitation practices among neonatal services (19).

There are some limitations to this study. As we only involved the directors of the participating centres, the actual practices of individual providers may not be represented. However, a consistent part of the infor-mation obtained in this survey is related to available equipment and intent to use different practices. This study involved only tertiary units, and the approach to delivery room management of ELBW infants can be different in level I and II Italian centres. However, the majority of ELBW infants in Italy were born at tertiary units. The data on ELBW infants who were re-suscitated in the centres were retrospectively collected limiting the quality of this information. Unfortunately, our questionnaire did not include questions regarding the survival rates in the surveyed centres. For this rea-son, we could not correlate the delivery room manage-ment with neonatal mortality.

F. Rech Morasutti, I. Satariano, N. Doglioni, et al.10

Conclusions

Our study assess the consistency of practice and the adherence to the International Guidelines in early DR management of ELBW infants in Italy. In general, the approach to the ELBW infants at birth shows a good compliance with the International Guidelines for Neonatal Resuscitation; particular attention is devoted to temperature control, use of oxygen and less-invasive respiratory support. However, there are marked geo-graphical differences in delivery room management of ELBW infants, and some relevant interventions are not uniformly followed by the surveyed centres. Fac-tors contributing to such discordance remain unclear and need to be investigated in future studies. In the meantime, effective educational interventions focused on the practice of neonatal resuscitation have to be supported.

Acknowledgements

We thank the heads of the participating centres for their assistance with this survey.

References

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11. de Vonderweid U, Spagnolo A, Corchia C, Chiandotto V,Chiappe S, Chiappe F, et al. Italian multicentre study on very low-birth-weight babies. Neonatal mortality and two-year outcome. Acta Paediatr 1994; 83: 391-6.

12. Horbar JD, Badger GJ, Lewit EM, Rogowski J, Shiono PH. Hospital and patient characteristics associated with varia-tion in 28-day mortality rates for very low birth weight in-fants. Pediatrics 1997; 99: 149-56.

13. Ronconi A, Corchia C, Bellu R, Gagliardi L, Mosca F, Za-nini R et al. Esiti dei neonati di basso peso nelle Terapie Intensive Neonatali partecipanti all’Italian Neonatal Net-work nel 2008. Istituto Superiore di Sanità. 2011, iii, 74 p. Rapporti ISTISAN 11/44.

14. World Health Organization. Managing newborn problems: a guide for doctors, nurses and midwives. WHO Library Cataloguing-in-Publication Data; 2003: C1-9.

15. McCarthy LK, Molloy EJ, Twomey AR, Murphy JF, O’Donnell CP. A randomized trial of exothermic mattresses for preterm newborns in polyethylene bags. Pediatrics 2013; 132: e135-41.

16. Lunze K, Bloom DE, Jamison DT, Hamer DH. The global burden of neonatal hypothermia: systematic review of a major challenge for newborn survival. BMC Medicine 2013; 11: 24.

17. Soll RF, Edwards EM, Badger GJ, Kenny MJ, Morrow KA, Buzas JS, et al. Obstetric and neonatal care practices for in-fants 501 to 1500 g from 2000 to 2009. Pediatrics 2013; 132: 222-8.

18. Schmolzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung PJ. Non-invasive versus invasive respiratory sup-port in preterm infants at birth: systematic review and meta-analysis. BMJ 2013; 374: f5980.

19. Mann C, Ward C, Grubb M, Hayes-Gill B, Crowe J, Mar-low N, et al. Marked variation in newborn resuscitation practice: A national survey in the UK. Resuscitation 2012; 83: 607-11.

Correspondance:Daniele Trevisanuto, MD, Children and Women Health Department, Medical School, University of Padua, Azienda Ospedaliera di Padova, Via Giustiniani, 3 35128 Padua, Italy.Tel. 39 049 8213545 - Fax: 39 049 8213502E-mail: trevo@pediatria.unipd.it

Respiratory management of ELGA infants in a region of Southern ItalyLetizia Capasso, Julia Cerullo, Laura Bucci, Angela Carla Borrelli, Roberta Caiazzo, Francesco RaimondiDivision of Neonatology, Department of Translational Medical Sciences, Università Federico II, Naples, Italy

Summary. The distribution of births in many regions of Southern Italy is scattered among a high number of level I centers, many of which still count less than 500 deliveries per year. Campania, the region around Na-ples, is no exception and this excessive fragmentation results in a high number of neonatal transports, many of which for respiratory distress. In the present paper, we review three different regional peculiarities relevant to the respiratory management of extremely low gestational age babies. (www.actabiomedica.it)

Key words: respiratory management, preterm, ELGA infants

Acta Biomed 2015; Vol. 86, Supplement 1: 11-15 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

With its 54 thousands yearly births, Campania, a southern region of Italy, accounts for 10.2 % of all Ital-ian neonates. When compared to the North and the whole country, Campania has (1):

- a gradually decreasing neonatal mortality rate (2,5‰ in 2013) that approximates the national aver-age (2,1‰ ) but still significantly higher than Lum-bardy (1,7‰ )

- a high number of level I birth centers that can assist only uncomplicated deliveries. In 2012 , level I centers were 56 accounting for 37.333 neonates while at the 14 Level II/III centers18.954 neonates were born.

- high number of caesarean section births (region-al average 60% of all deliveries)

- high number of neonatal transports (about 1.500 neonates transported each year).

Indeed, there is sufficient evidence in the litera-ture to believe that the above variables are connected in a network of questionable efficacy and efficiency.

The aim of this paper is to review those critical features of respiratory management of preterm and

particularly of extremely low gestational age babies (ELGA 23-28 weeks) that might result from the pre-sent organizational pattern .

Respiratory assistance during transport of ELGA neonates

Three dedicated neonatal transport systems are si-multaneously active serving an area of 13 670,95 km² and a population close to 6 million inhabitants. The already cited scattering of births contributes to a 2.6% global transportation index (a 1% index is considered the desired standard). Our transport team (Università Federico II) operated slightly more than half the 1446 transports from January 2012 and December 2013.

During this interval, 7.2 % of transported infants had a GA less than 30 weeks, a percentage that had been substantially stable across the years. When con-sidering transported infants in need of respiratory sup-port, out of a total 662 infants, 9% of were had a GA less than 30 weeks. This percentage was lower than the 11.8% recorded for the same class in the period 2004-2007.

L. Capasso, J. Cerullo, L. Bucci, et al.12

As per the respiratory assistance mode during transport in the 2012-2013 period, 20 ELGA neo-nates received IPPV, 5 had nasal CPAP and 9 had plain oxygen therapy in the incubator.

While we detect a trend in decreasing the trans-ports of ELGA neonates along the years, we affirm that the optimal result would be no transport at all. Low gestational age confers an additional risk of mov-ing a baby from her/his birthplace. The low intensity of respiratory support offered to 14/34 neonates speaks in favour of relatively stable conditions and possibly short trips. One more reason to suggest birth centrali-zation to our health policy makers.

Data from the Campania section of the Vermont Oxford Database

The latest, 2013, ELGA cohort available from the Campania section of the Vermont Oxford Network (VON) consists of 208 preterm infants between 22-29 weeks gestational age (Table 1). Their mean mortality 30.3% (IC: 22.2 – 33.3%) was higher than the Ital-ian section of VON (Italian Neonatal Network, INN) that shows a mean mortality of 22.7% (IC: 14.3-30.6). Considering infant characteristics at admission, 87.4% of babies are inborn (INN: 90.5%), 82.5 % received prenatal care (INN: 90.3%), chorioamnionitis rate is 13% (INN: 19.1%), maternal hypertension 21.4%

(INN: 18.2%), antenatal steroids were used for 60.4% of babies (INN: 80.3%), 15.3% of babies were SGA (INN: 12.4%).

Looking at the initial resuscitation in delivery room of such small babies, in Campania the mean incidence of Apgar score < 4 at five minutes of live was 5.7% simi-lar to the INN incidence (6.1%). Delivery room deaths were 2.3% in Campania and 1.5% in Italy. The delivery room resuscitation management in Campania included: face mask ventilation 50% (INN: 72.1%), cardiac com-pression 14% (INN: 9.8%), surfactant 11.3% (INN: 21.8 %), epinephrine 10.3 % (INN: 4.9%), intuba-tion 73.4% (INN: 57%), oxygen 80.4% (INN: 85.6%), CPAP in delivery room: 13.6% (INN: 39.4%).

Respiratory distress syndrome was diagnosed in 96.2% of these babies in the Campania cohort (90.2% INN).

Mechanical ventilation was used for 88.6% of ba-bies during hospital staying (conventional 86.2%, high frequency 46.7%) in Campania while INN data show that mechanical ventilation was used for 73.2% of ba-bies during hospital staying (conventional 68.7%, high frequency 28.5%).

In Campania, CPAP was used for 69.5% of ba-bies during hospital staying ( but CPAP before intu-

Table 1. Respiratory care during neonatal transport in Cam-pania for 2012 - 2013 compared with years 1995 - 2007. Data from University “Federico II” neonatal transport database

Table 2. Transported neonates requiring respiratory care di-vided by GA for 2012 - 2013 compared with years 2004 - 2007. Data from University “Federico II” neonatal transport database

Respiratory management of ELGA infants in a region of Southern Italy 13

bation only 24.8%) while in the INN cohort CPAP was applied to 77.4% babies during hospital staying (and 48.7% before intubation). High flow nasal can-nula was used for 8.6% (INN: 30.3%) babies and nasal IMV/SIMV 25.7% neonates (INN: 31.6%)

Surfactant at any time during hospital staying was administered to 85.8% of babies in Campania and 74.7% in the INN. In Campania 63.8% of babies have received surfactant in the first 2 hours of life (INN: 44%).

While the incidence of pneumothorax (2.9% IC: 0-5.9%) was significantly lower than the INN data (5.2% IC: 0-8.1%), both the incidence of chronic lung disease (Campania 29.5% vs INN 26.1% ) and the use of steroids for chronic lung disease (Campania 17.9% vs INN 17.3%)) were comparable. Inhaled nitric ox-ide was used for 1% of babies in Campania and for 5% in the INN. In the year 2013, 6.1% of babies were

discharged home on oxygen in Campania (8.9% for INN).

Taken together, the data suggest that ELGA in-fants are being born in suboptimal conditions in our region. In fact, figures from the Campania VON sec-tion (including data from 10 of 15 NICUs), show less prenatal care, much less antenatal steroids, have higher frequency of maternal hypertension and SGA com-pared to INN. All these conditions may contribute to explain the higher mortality rate, the more aggressive respiratory approach in the delivery room manage-ment and in the respiratory management during hos-pital stay of ELGA infants in Campania. Converse-ly, the lower figures for pneumothorax in Campania might be related to a less extensive use of N-CPAP with reduced mean airway pressure.

Strategies to improve outcomes of ELGA infants need to improve both prenatal care, and the use of pre-

Table 3. Characteristics of preterm infants with GA 22 - 29 weeks included in the Campania section of VON compared to the Italian group of VON (INN)- year 2013

VON Campania (N = 208) NN (N = 2.187)

Mortality 30,3% 22,7% Inborn 87.4 90.5 Prenatal care 82.5 90.3 Chorioamnionitis 13% 19.1% Maternal hypertension 21.4% 18.2% Antenatal steroids 60.4% 80.3% Apgar score <4 at 5’of life 5,7% 6,1% SGA 15.3% 12.4% Delivery room deaths 2,3% 1,5% Face mask in delivery room 50% 72,1% Cardiac compression in delivery room 14% 9,8% Surfactant in delivery room 11,3% 21,8% Epinephrine in delivery room 10,3% 4,9% Intubation in delivery room 73,4% 57% Oxygen in delivery room 80,4% 85,6% CPAP in delivery room 13,6% 39,4% Respiratory distress syndrome 96,2% 90,2%Mechanical ventilation 88,6% 73,2% N-CPAP during hospital staying 69,5% (N-CPAP before intubation 24,8%) 77,4% (N-CPAP before intubation 48.7%) High flow nasal cannula 8,6% 30,3% Nasal IMV/SIMV 25,7% 31,6% Surfactant at any time 85,8% (in the first 2 hours of life 63,8%) 74,7% ( in the first 2 hours of life 44%) Pneumothorax 2,9% 5,2% Chronic lung disease 29,5% 26,1% Steroids for chronic lung disease 17,9% 17,3% Inhaled nitric oxide 1% 5% Babies discharged home with oxygen 6,1% 8,9%

L. Capasso, J. Cerullo, L. Bucci, et al.14

natal steroids. The transportation of such immature in-fants should become an exceptional event by promot-ing “in utero” transport of all at risk of preterm birth to an adequate number of NICU beds.

At the same time, neonatologists needs to put all efforts to implement the systematic application of early non-invasive ventilation starting from the deliv-ery room with selective surfactant administration and rapid extubation to reduce rates of mechanical ventila-tion, postnatal steroid therapy and ultimately chronic lung disease as recently recommended by AAP (2).

Use of Bi-level vs nasal CPAP as a respiratory support mode after extubation of VLBW and ELGA infants

Finally, we present the preliminary data from a retrospective study conducted in the NICU of the University “Federico II” in Naples, from January 2009 to December 2013. Although all VLBW infants in-tubated at birth were enrolled in this study, for the purpose of this paper we also extrapolated the data of ELGA infants.

The study primary aim was to compare the rate of failure of nCPAP (PEEP 4-5 cm H2O) versus bi-level (PEEP 4-5, PIP 7-8 cm H2O, it 0.7-1, rate: 10-40/min) as non-invasive respiratory support after extubation of VLBW infants with respiratory distress syndrome. Failure of n-cpap and bi-level was defined as the need of more intensive respiratory support (bi-level or intubation and mechanical ventilation for the nCPAP group and intubation and mechanical ventila-tion for the bi-level group). The indications to switch to a higher intensity of respiratory support were: wors-

ening of clinical signs of RDS, inability to maintain oxygen saturation between 85-95% and respiratory ac-idosis (pH < 7.25 and PaCO2 > 65 mmHg). Second-ary outcomes were: rate of failure of nCPAP versus Bi-PAP within the first week from extubation, mortality, pneumothorax, PVL, BPD and ROP at discharge; 146 babies were enrolled (97 in n-cpap group; 49 in bi-lev-el group). No difference was found in the demographic variables except for birth weight and gestational age (GA): 1.071 ± 246 gr, GA 29± 1.9 in nCPAP group vs 854 ± 229, GA 27.5 ± 2.7 in bi-level group (Tab. 1). Extubation failure during the first week was more fre-quent in n-cpap group: 25/97 (25.7%) vs 5/49 (10.2%) in bi-level group (p<0.05) (table 1). Extrapolating data for infants between 22 – 29 weeks of GA, 22/34 babies (64.7%) in n-cpap group vs 5/20 (25%) in bi-level group (p<0.05) failed extubation during the first week (graph 1). No difference was found for the other out-comes for infants between 22-29 weeks of GA.

The early use of nasal ventilation has been exten-sively promoted in the last decade starting from deliv-ery room resuscitation (4) and different modes of sup-port have been proposed. Beyond the classical nCPAP, the BiPAP, i.e. two different nasal pressure during spontaneous respiration, has gained popularity. Un-like CPAP, BiPAP may generate a tidal volume that improves gas exchange. On the other hand, the success of BiPAP over n-CPAP in our setting may be related to the higher mean airway pressure delivered without difference in rate of pneumothorax. This is in keeping with the recent observation by Buzzella studying very preterm infants (23-30 weeks) that higher distending

Table 4. Main characteristics and extubation failure rate within first week in preterm neonates assisted in n-cpap versus bi-level n-cpap (BiPAP) after extubation

nCPAP BiPAP p

GA (wks) 29±1.9 27.5±2.7 <0.05

BW (gr) 1.071±246 854±229 <0.05

Extubation failure 43 23 0.766

Extubation failure within 25 5 <0.05the first week

Graph 1. Extubation failure within first week for preterm in-fants between 22 - 29 weeks of GA assisted in nCPAP vs Bi-PAP after extubation

Respiratory management of ELGA infants in a region of Southern Italy 15

pressures are needed post– extubation for the more immature infants (3).

In 2010 Lista in a small RCT showed that pre-term babies assigned from birth to bi-level compared with n-cpap for treatment of RDS had less need of respiratory support and fewer oxygen dependency days (5). In the same year, Ancora et al published a retro-spective study showing that bi-level compared with nCPAP reduced the need for mechanical ventilation in the 7 days after Insure failure in VLBW infants (6). Recently, an Italian RCT in VLBW infants showed no statistically significant differences for bi-level com-pared with nSIPPV as primary treatment of RDS in the first 2 hours of life in terms of duration of ventila-tion and failure, suggesting that both NIV techniques are effective in the early treatment of RDS in VLBW infants (7).

Given the relatively high number of VLBW who are still mechanically ventilated, a direct comparison post extubation of nasal ventilation techniques was needed. Our data, although retrospective, contribute to fill this gap together with future larger, prospective studies.

References

1. Università di Napoli Federico II. Regione Campania. “Rap-porto sulla Natalità in Campania anno 2012”. http://www.epicentro.iss.it/problemi/percorso-nascita/pdf/pdf%20rap-porto%202012.pdf

2. AAP Committee on Fetus and Newborn. Respiratory Sup-port in Preterm Infants at Birth. Pediatrics 2014; 133; 171.

3. Buzzella B, Claure N, D’Ugard C, Bancalari E. A Rand-omized Controlled Trial of Two Nasal Continuous Positive Airway Pressure Levels after Extubation in Preterm Infants. The Journal of Pediatrics 2014; 164: 46.

4. Capasso L, Capasso A, Raimondi F, Vendemmia M, Araimo G, Paludetto R. A randomized trial comparing oxygen de-livery on intermittent positive pressure with nasal cannulae versus facial mask in neonatal primary resuscitation. Acta Paediatr 2005 Feb; 94 (2): 197-200.

5. Lista G, Castoldi F, Fontana P, Daniele I, Cavigioli F, Rossi S, Mancuso D, Reali R. Nasal continuous positive airway pressure (CPAP) versus bi-level nasal CPAP in preterm ba-bies with respiratory distress syndrome: a randomised control trial. See comment in PubMed Commons below. Arch Dis Child Fetal Neonatal Ed 2010 Mar; 95 (2): F85-9.

6. Ancora G, Maranella E, Grandi S, Pierantoni L, Guglielmi M, Faldella G. Role of bilevel positive airway pressure in the management of preterm newborns who have received surfactant. Acta Paediatr 2010 Dec; 99 (12): 1807-11. doi: 10.1111/j.1651-2227.2010.01910.x.

7. Salvo V, Lista G, Lupo E, Ricotti A, Zimmermann LJ, Gavilanes AW, Barberi I, Colivicchi M, Temporini F, Gaz-zolo D. Non invasive ventilation strategies for early treat-ment of RDS in preterm infants: an RCT. Pediatrics 2015 Mar; 135 (3): 444-51.

Correspondance:Letizia Capasso, MD PhD, Division of Neonatology, Department of Translational Medical Sciences, Università Federico IIvia Sergio Pansini 580131 Naples, Italy

German experience in the management of ELGAN infantsHans FuchsNeonatology and Ped. Intensive Care, Center for Pediatrics, University of Freiburg, Germany

Summary. Of 680 000 infants born in Germany a year roughly 10% are preterm and 1% are very preterm. They are treated in around 150 level 1 perinatal centers and there are various credos how to best treat the EL-GAN infant. However, many centers include the use of a sustained inflation for lung aeration in the standard protocol of delivery room care in Germany. As a result of the large studies on delivery room care, a trend for earlier or prophylactic surfactant in the most immature infants can be observed, however, surfactant is in-creasingly given in a new less invasive way called LISA. German randomized controlled trials on LISA , on permissive hypercapnia in the premature infants and a German initiated European trial on inhaled steroids have been completed and preliminary results are available. NIRS so far mostly is used for research reasons; however, the number of centers that monitor brain oxygenation for clinical reasons to guide hemodynamic management is increasing. A recent initiative was able to tremendously reduce the rate of IVH by prospective multidisciplinary surveillance. (www.actabiomedica.it)

Key words: surfactant, sustained lung inflation

Acta Biomed 2015; Vol. 86, Supplement 1: 16-20 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

Survival of ELGA newborns (ELGAN) has in-creased notably over the past years, however, rates of long term sequel like bronchopulmonary dysplasia and neurologic impairment have not improved satisfyingly. Optimal respiratory and cardiovascular management in the very first hours and days of life is the mainstay to avoid such complications. However, despite the grow-ing number of large trials there is still lack of knowl-edge about the best approach for the individual infant. Evidence and clinical experience have to be merged for a better outcome. Various approaches have been tested in Germany in the recent years:

Delivery room (DR) care:

In the early nineties the application of a sustained inflation to facilitate the adaptation to postnatal life was introduced into German neonatal units empirical-ly by Wolfgang Lindner and Frank Pohlandt from Ulm

(1,2). It was not until ten years later, that the rationale and benefit of this approach was studied in more detail. Prenatally the lung of the fetus is filled with lung fluid causing a high resistance of the newborns airways. te Pas et al. were able to visualize in the premature rab-bit model that a long lasting inflation of more than 10 seconds is able to move the water column into the peripheral parts of the lungs, from where it is taken up into the lung interstitium (3,4). The resulting high functional residual capacity, the proposed homogenous lung aeration and the lower systemic inflammatory response compared to single breaths lung aeration in this animal model is attractive. Indeed a recent Italian study was able to proof a lower need for intubation after sustained inflation (5) and almost 30% German centers have adopted this policy (6-8). Furthermore, sustained inflations are easy to apply and effective in stabilization the infant in the DR. However, second-ary outcomes from the above study, and retrospective data from a single center associate air leaks with the application of sustained inflation, therefore, caution

German experience in the management of ELGAN infants 17

using this procedure may be advised (5,9). Sustained inflations are currently tested in a large international trial (SAIL-trial) (10).

Indication of surfactant therapy and/or invasive ventilation

Avoidance of mechanical ventilation by the use of early noninvasive support was a mainstay in the sup-port of ELGANs in Germany. However, large scale international delivery room randomized controlled trials failed to identify significant benefits of this ap-proach compared to the classical approach with intu-bation in the DR (11-14). Unexpectedly, a somewhat higher incidence of airleaks was observed with the noninvasive approach, especially if high thresholds for intubation were applied (11). Likely, this results from negative effects of late surfactant therapy in the course of moderate to severe surfactant deficiency. Would it be more advantages to treat all infants with surfactant very early? Prophylactic surfactant therapy translated not into better outcomes (15). Some infants will not need surfactant therapy and may be treated unneces-sarily. Most infants with early CPAP success without surfactant require very little or no additional oxygen for respiration (8). Identification of infants in need of surfactant identified at low FiO2 thresholds (0.3-0.4) and treatment without delay as soon as certain thresh-olds are met may be a key strategy to optimize respira-tory outcomes.

Mode of surfactant application

The classic approach to deliver surfactant is in-tubation and surfactant therapy followed by mechani-cal ventilation. Attempts to deliver surfactant non-invasively by inhalation (16) or via the pharynx were hampered by low surfactant deposition. The high lipid/phospholipids content impedes nebulization. Angela Kribs from Cologne introduced in 2003 a new method to deliver surfactant through a very thin gastric tube into the trachea during spontaneous breathing (17). This approach which is now called LISA (Less Invasive Surfactant Application) recently was tested in three randomized controlled trials (RCT)s. The AVM trial in infants 26-28 weeks GA showed shorter duration

of mechanical ventilation and less oxygen demands at age 28 days, however no benefit in mortality or rate of bronchopulmonary dysplasia (BPD) (18). The Take Care study compared surfactant therapy by INSURE (Intubation, Surfactant, Extubation) and LISA (19). The need for mechanical ventilation in the first 72 hours of life and the rate of BPD was significantly lower in the LISA group when compared with the In-SurE group. The NINSAPP trial tested if this form of surfactant delivery is suitable for very premature in-fants. Infants of 23 + 0/7 to 26 + 6/7 weeks GA were randomized to LISA or surfactant therapy followed by mechanical ventilation. No difference in death or rate of BPD was found, however, the rate of intraventricular hemorrhage (IVH) was lower in the LISA group ((20)Tab. 1). LISA may in future proof to be non inferior or even superior to the classical surfactant application. Despite the sparse safety data being available, LISA is increasingly used in Germany. Data from the Ger-man neonatal network have recently been published. Between 2009 and 2012, 1103 infants <32 weeks have been treated with LISA in the network. Compared to matched controls rates of BPD, mechanical ventilation but not IVH were decreased (21).

Gentle ventilation

Despite new noninvasive modes to deliver sur-factant up to 50% of infants may finally require inva-sive ventilation. Therefore, techniques to avoid ventila-tor induced lung injury are mandatory, if low rates of chronic lung disease or death are wanted. A potential strategy to decrease ventilatory needs and by this at-tenuate lung injury is to allow for a moderate level of hypercapnia. Ulrich Thome from Leibzig recently per-formed a German multicenter randomized controlled trial in preterm infants of 23-28 weeks GA to study the effects of permissive hypercapnia in ELGANs who

Table 1. NINSAPP trial (20)

Control Lisa p-value (n=104) (n=107)

Death 12 (12) 10 (9) 0.59BPD 31 (30) 25 (23) 0.34IVH 41 (39) 26 (24) 0.017IVH>II° 23 (22) 11 (10) 0.019

H. Fuchs18

required intubation and ventilation. A PCO2 of 55-65 mm Hg was targeted in the permissive hypercapnia group and compared to 40-50 mm Hg in the standard group. In both groups pCO2 increased in steps by 5 mm HG after the fourth day. 359 infants of 23 + 0/7 to 27 + 6/7 weeks GA were included before the trial was stopped early because of futility. Preliminary results of the interims analysis have recently been published (22, Table 2): No difference in the rate of BPD and death (36% vs 30%) were found. The rates of IVH were simi-lar. Therefore, increasing the PCO2 targets may not be helpful and lung protective in the majority of infants. However, allowing for some more moderate degree of hypercapnia in cases of severe lung disease seems to be tolerated well without affecting the rate of intraven-tricular hemorrhage or other outcomes.

Inhalative steroid treatment

Early postnatal steroids attenuate lung inflamma-tion, improve pulmonary function, facilitate extubation and decrease the rate of BPD and/or death. However, systemic steroids have been linked to adverse neuro-logic outcome. Therefore, high dose steroid therapy of the preterm infant needs to be restricted to the sickest infants in very severe respiratory distress. Dirk Bassler from Tübingen addressed in his large scale European randomized trial (NEUROSIS) the question, if in-haled steroids may prevent chronic lung disease with-out affecting neurologic outcome negatively. Infants 23 + 0/7 to 27 + 6/7 were randomized to inhalative budesonide or placebo within the first 12 h of life and continued as long as additional oxygen was neces-sary. Preliminary results have recently been published (23;24). Inhalation of steroids significantly reduced the rate of BPD (Table 3). However, the effect was very modest and the rate of BPD or death was reduced by

6% only. Inhalation of steroids may not be the magic bullet to improve long term respiratory outcome.

Near infrared spectroscopy in the delivery room

Studies from Ulm (25) and Graz (26,27) describe the use of near infrared spectroscopy to assess regional cerebral oxygenation in the delivery room. Knowledge of the regional organ oxygenation may help to monitor adequate oxygen supply of the newborns brain which relies on arterial oxygenation, and oxygen carriers, but also on cerebral perfusion and cerebral metabolism. Percentiles of oxygen cerebral oxygenation during tran-sition have been described in preterm and term infants. Some infants that later developed IVH had low cerebral oxygenation during and after delivery room care de-spite an arterial oxygen saturation within normal limits. Therefore, low cerebral blood flow very early in post-natal life may cause low tissue oxygenation which may precede IVH. Gorm Greisen from Copenhagen tested in a multicenter pilot RCT in 166 infants <28 weeks GA if cerebral oxygenation can be held within certain target ranges (55-85%) by adjusting various factors i.e. FiO2, cardiac output or hematocrit (28). Cerebral oxygenation (primary outcome) was outside the recom-mended range for 36.1 (9.2-79.5%) % hours compared with 81.3 (38.5-181.3) % hours in the control group. Most exiting was the fact that brain damage (secondary outcome) was strikingly lower in the NIRS group (13 vs 23% severe brain injury). Interestingly >80% of ac-tions taken to correct cerebral oxygenation was adjust-ment of FiO2. NIRS, therefore, may in future help to improve outcomes and lowering the rate of IVH.

Intraventricular hemorrhage

Intraventricular hemorrhage is a major threat and the main risk factor for adverse neurologic outcome. It

Table 2. Phelbi Trial (22); interims analysis

Permissive Control p-value Hyperkapnia (n=156) (n=156)

BPD or Death 57 (38%) 51 (35%) n.s. IVH 53 (34%) 55 (36%) n.s. IVH3-4 21 (14%) 15 (10%) n.s.

Table 3. Neurosis Trial (24)

Control Budesonide p-value (n=419) (n=437)

BPD or Death 194 (46.3%) 175 (40%) 0.053 Death 57 (13.6%) 74 (16.9%) -Survival with BPD 138/363 (38%) 101/363 (27.8%) -

German experience in the management of ELGAN infants 19

affects foremost the extremely immature and sickest preterm infants. Various risk factors like immaturity, low blood pressure, sepsis have been associated with IVH, however, very little therapeutic options have arisen from this knowledge. Helmut Hummler from Ulm recently introduced an effective approach to low-er rates of IVH (29). In this IVH initiative in the first step risk factors for IVH were identified by literature research. Furthermore, centers with known low rates of IVH were visited to identify potentially better prac-tices. From this a bundle of practices were identified. Examples of these practices included: late cord clamp-ing, no allowance of hypotension for >1h, early sur-factant therapy without any delay, normocapnia, strict minimal handling policy. Adherence to these practices was henceforward in detail prospectively monitored for any preterm infant. Furthermore, each clinical course was discussed in an interdisciplinary conference of neonatologists, obstetrician and nurses on a weekly base. As a consequence overall rates of IVH decreased in infants <1500g birth weight from 22% to 10%, in infants <1000 g from 29% to 15% and in preterm in-fants <28 weeks from 34 to 16% (Table 4). None of the identified practices was new: It seems rather that the most important factor for the observed decrease in IVH rate was the multidisciplinary and standardized approach in addition to high guideline adherence as a result of the continuous surveillance.

References

1. Lindner W, Hogel J, Pohlandt F. Sustained pressure-con-trolled inflation or intermittent mandatory ventilation in pre-term infants in the delivery room? A randomized, controlled trial on initial respiratory support via nasopharyngeal tube. Acta Paediatr 2005; 94(3): 303-309.

2. Lindner W, Vossbeck S, Hummler H, Pohlandt F. Deliv-ery room management of extremely low birth weight in-fants: spontaneous breathing or intubation? Pediatrics 1999; 103(5 Pt 1): 961-967.

3. te Pas AB, Siew M, Wallace MJ et al. Effect of sustained inflation length on establishing functional residual capacity at birth in ventilated premature rabbits. Pediatr Res 2009; 66(3): 295-300.

4. te Pas AB, Siew M, Wallace MJ et al. Establishing func-tional residual capacity at birth: the effect of sustained infla-tion and positive end-expiratory pressure in a preterm rabbit model. Pediatr Res 2009; 65(5): 537-541.

5. Lista G, Boni L, Scopesi F et al. Sustained lung inflation at birth for preterm infants: a randomized clinical trial. Pedi-atrics 2015; 135(2): e457-e464.

6. Roehr CC, Grobe S, Rudiger M et al. Delivery room man-agement of very low birth weight infants in Germany, Aus-tria and Switzerland--a comparison of protocols. Eur J Med Res 2010; 15(11): 493-503.

7. Mehler K, Grimme J, Abele J, Huenseler C, Roth B, Kribs A. Outcome of extremely low gestational age newborns af-ter introduction of a revised protocol to assist preterm in-fants in their transition to extrauterine life. Acta Paediatr 2012; 101(12): 1232-1239.

8. Fuchs H, Lindner W, Leiprecht A, Mendler MR, Hummler HD. Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventila-tion in preterm infants of <29 weeks gestational age. Arch Dis Child Fetal Neonatal Ed 2011; 96(5): F343-F347.

9. Hummler HD, Parys E, Mayer B, Essers J, Fuchs H, Schmid M. Risk Indicators for Air Leaks in Preterm In-fants Exposed to Restrictive Use of Endotracheal Intuba-tion. Neonatology 2015; 108(1): 1-7.

10. Foglia EE, Owen LS, Thio M et al. Sustained Aeration of Infant Lungs (SAIL) trial: study protocol for a randomized controlled trial. Trials 2015; 16: 95.

11. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very pre-term infants. N Engl J Med 2008; 358(7): 700-708.

12. Sandri F, Plavka R, Ancora G et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010; 125(6): e1402-e1409.

13. Finer NN, Carlo WA, Walsh MC et al. Early CPAP ver-sus surfactant in extremely preterm infants. N Engl J Med 2010; 362(21): 1970-1979.

14. Dunn MS, Kaempf J, de KA et al. Randomized trial com-paring 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011; 128(5): e1069-e1076.

15. Sandri F, Plavka R, Ancora G et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010; 125(6): e1402-e1409.

16. Minocchieri S, Knoch S, Schoel WM, Ochs M, Nelle M. Nebulizing poractant alfa versus conventional instillation: Ultrastructural appearance and preservation of surface ac-tivity. Pediatr Pulmonol 2014; 49(4): 348-356.

17. Kribs A, Pillekamp F, Hünseler C, Bauerfeld C, Vierzig A.

Table 4. Surveillance to reduce IVH (29)

Rate of severe IVH Rate of severe IVH prior to intervention after intervention N=263 N=191

<24 weeks GA 26.9% 15.4% 24–25 SSW 18.3% 6.3% 26–27 SSW 8.3% 4.2% 28–29 SSW 0% 0% Total 9.1% 3.7%

H. Fuchs20

29th annual meeting of the Society for Neonatology and Pediatric Intensive Care 2003 jul 3–5 Cologne, Germany. Z Geburtsh Neonatol 2003; 207: S4.

18. Gopel W, Kribs A, Ziegler A et al. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breath-ing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 2011; 378(9803): 1627-1634.

19. Kanmaz HG, Erdeve O, Canpolat FE, Mutlu B, Dilmen U. Surfactant administration via thin catheter during spon-taneous breathing: randomized controlled trial. Pediatrics 2013; 131(2): e502-e509.

20. Kribs A, Roll C, Gopel W et al. Eine endotracheale Sur-factantgabe unter CPAP-unterstützter Spontanatmung optimiert das Outcome extrem unreifer Frühgeborener Ergebnisse der NINSAPP-Studie (Non Intubated Sur-factant Application). Monatsschrift Kinderheilkunde 2013; Supplement 1: -FV-34.

21. Gopel W, Kribs A, Hartel C et al. Less invasive surfactant administration is associated with improved pulmonary out-comes in spontaneously breathing preterm infants. Acta Paediatr 2015; 104(3): 241-246.

22. Thome U, Genzel-Boroviczény O, Bohnhorst B et al. Per-missive Hyperkapnie bei extrem untergewichtigen Frühge-borenen. Monatsschrift Kinderheilkunde 2013; 161 (Sup-plement1): FV33.

23. Bassler D, Halliday HL, Plavka R et al. The Neonatal Eu-ropean Study of Inhaled Steroids (NEUROSIS): an eu-funded international randomised controlled trial in preterm infants. Neonatology 2010; 97(1): 52-55.

24. Bassler D, Carnielli V, Halliday H et al. Early inhaled cor-ticosteroids for the prevention of bronchopulmonary dys-

plasia in extremely preterm infants: the neonatal European study of inhaled steroids (NEUROSIS). Arch Dis Child 2014; IS-003.

25. Fuchs H, Lindner W, Buschko A, Almazam M, Hummler HD, Schmid MB. Brain oxygenation monitoring during neonatal resuscitation of very low birth weight infants. J Perinatol 2012; 32(5): 356-362.

26. Pichler G, Binder C, Avian A, Beckenbach E, Schmolzer GM, Urlesberger B. Reference ranges for regional cerebral tissue oxygen saturation and fractional oxygen extraction in neonates during immediate transition after birth. J Pediatr 2013; 163(6): 1558-1563.

27. Urlesberger B, Kratky E, Rehak T et al. Regional oxygen saturation of the brain during birth transition of term in-fants: comparison between elective cesarean and vaginal de-liveries. J Pediatr 2011; 159(3): 404-408.

28. Hyttel-Sorensen S, Pellicer A, Alderliesten T et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. BMJ 2015; 350: g7635.

29. Schmid MB, Reister F, Mayer B, Hopfner RJ, Fuchs H, Hummler HD. Prospective risk factor monitoring reduces intracranial hemorrhage rates in preterm infants. Dtsch Ar-ztebl Int 2013; 110(29-30): 489-496.

Correspondance:Hans Fuchs, MD, PhD Neonatology and Ped. Intensive Care, Center for Pediatrics, University of Freiburg, Germany

Obstetrical management of fetus with intra uterine growth restriction (IUGR) and late IUGREnrico Ferrazzi, Daniela Casati, Sara Zullino, Eleonora RostiClinica Ostetrica e Ginecologica, Dipartimento di Scienze Biomediche e Cliniche, Università degli Studi di Milano

Summary. In this article we evaluated an important complication of pregnancy, the fetal growth restriction (IUGR). IUGR is defined as an estimated fetal weight of fetal abdominal circumference below the 10th centile measured by ultrasound according to local standards. We present the prenatal surveillance, the screening tests for late IUGR and the new diagnostic examinations, to establish the best prevention system for IUGR and late IUGR. (www.actabiomedica.it)

Key words: fetal growth restriction (IUGR); late IUGR; screening test

Acta Biomed 2015; Vol. 86, Supplement 1: 21-23 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

An important complication of pregnancy is fetal growth restriction. A widely accepted prenatal defini-tion of intra uterine growth restriction (IUGR) is de-fined as an estimated fetal weight of fetal abdominal circumference below the 10th centile measured by ul-trasound according to local standards.

Perinatal mortality are increased in late preterm and term fetuses with a birth weight below the 10th population percentile. About 60% of term perinatal mortality regards children with a birth weight per-centile below the 10th percentile. Yet, beyond perinatal this burden of mortality and perinatal morbidity what mostly concern clinicians are the consequences of low birth weight on for future development, especially for cardiovascular, metabolic and neurological develop-ment. (‘Barker hypothesis’). It is know that adverse insults acting during intrauterine life can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased

risk of disease in adulthood. The “fetal origin of adult disease Hypothesis” by Barker et al identified the re-lationship between impaired intra-uterus growth and adult cardiovascular disease risk and death.

Fetal Programming

According to Rogers, Lillycrop and others, “the foetus appears to use the in utero environment to pre-dict and prepare for the postnatal environment. That is, an organism alters its developmental path to produce a phenotype (observable traits, such as characteristics of behaviour, physiology, metabolism, or outward appear-ance) that gives it a survival or reproductive advantage in postnatal life”. This process goes by the name of “ predictive adaptive response”. Epigenetics is the key to understanding the relationship between intrauterine environment and gene expression.

The placenta bears a central role in fetal program-ming. The placenta is the organ that the fetus uses dur-ing intrauterine life to transfer nutrients, and energetic

E. Ferrazzi, D. Casati, S. Zullino, E. Rosti22

substrates from maternal blood diverted in the inter-villuos space, to exchange gases and hormones. The determinant of these processes is trophoblast devel-opment both as an anatomic organ which accommo-dates maternal and fetal blood flow and a membrane exchange activity.

The aetiology of fetal growth restriction is mul-tifactorial. The most common cause for fetal growth problems is a disturbance in the utero-placenta circu-lation. This disturbance develops in a slow process, but without intervention it can lead to fetal death. Insuf-ficiency of the utero-placenta circulation is often as-sociated with pregnancy induced hypertension and pre-eclampsia. Maternal diseases like hypertension, renal failure or pulmonary disease are associated with a higher risk of IUGR. Tobacco, drugs and alcohol also are associated with a higher risk of IUGR, where smoking is the most important negative factor. Other related factors are a low socio-economical status, stress, poor diet and maternal age (very young women and a high maternal age). Foetuses with congenital or ge-netic abnormalities are also at a higher risk for IUGR. The most important risk factors are medical diseases; especially hypertensive disorders, smoking and com-plications in a previous pregnancy.

Prenatal Surveillance

Antepartum fetal surveillance is essential in man-aging these pregnancies and timely recognition of com-plications. Term, growth restricted foetuses present the obstetrician with at least two difficulties. Firstly they are difficult to identify. After identification of the small fetus, the second challenge concerns, the distinc-tion between pathologically small foetuses, most likely accompanied by a suboptimal placental function, and constitutional healthy small foetuses. Such a distinc-tion is difficult, since most assessment tools fail dur-ing the term period. Umbilical artery Doppler fails in recognizing the fetus with true growth restriction at near term or term age. Similarly, Doppler velocimetry of the uterine arteries although more sensitive in the identification of the risk of small placentas is still just a proxy of the real maternal vascular supply line to the placenta. In spite of these limitations ultrasound meas-urements of the abdominal circumference and Uterine

Doppler velocimetry could be considered for screening late IUGR foetuses

Screening tests for late IUGR

1. Cross sectional Abdominal circumference measurement below the 10th percentile does not rep-resent growth, yet it represents a robust reproducible screening test between 35+0 and 37+6 wks’gestation. Intrauterine death due to growth restriction before 37+6 weeks is an exceptional event and therefore this window of gestation represent a proper timing of screen out abnormal fetal growth before delivery.

2. Uterine Doppler velocimetry in late gestation might identify foetuses at risk of IUGR due to pla-cental vascular insufficiency, that might be lost by fetal biometry.

When recognized, another challenge is formed by limited therapeutical options. The only possible in-tervention consists out of adequately timing of birth. Optimal timing of elective delivery is difficult in preg-nancies complicated by intra uterine growth restriction due to lack of adequate diagnostic tools. The impor-tance of being able to identify foetuses at risk resides in the possibility to target interventions with poten-tial adverse effects if used too liberally. This has been shown by a recent large randomized trial in which an unselected population of term foetuses with an es-timated fetal weight below the 10th percentile were randomized between immediate induction of labor or expectant management. The incidence of adverse out-comes did not differ between both groups. In other words, too many constitutionally small foetuses were exposed to an unnecessary intervention with risks of complications obscuring the possible gain of early in-tervention in foetuses at real risk.

Many parameters have been evaluated to distin-guish between constitutionally small and pathologi-cally growth restricted foetuses with little result so far. Doppler evaluation of flow patterns in the umbilical artery are used routinely in preterm growth restricted foetuses but are normal in most cases in term small-for-gestational-age foetuses. This due to the fact that a high placental resistance occurs only when more than 1/3rd of placenta function is deficient. Oligohydram-nios is not specific enough. Abnormal fetal heart rate

Obstetrical management of fetus with IUGR and late IUGR 23

patterns can reliably identify fetal distress but are a late sign of impairment. Monitoring of fetal movements is subjective and reduced movements are generally also a late sign of impairment

Recently a number of new diagnostics tools have been described in small case series, which have poten-tial in the early recognition of the term IUGR fetus at risk for adverse neonatal outcome:

New diagnostic examinations

1. Blood flow volume in the uterine artery as-sessed with Doppler ultrasound seem to be more sen-sitive than just the arterial Doppler waveform .

2. Blood flow volume in the umbilical vein can sort out minor reduction in nutritional function of the placenta notwithstanding normal Umbilical artery waveform.

3. PGF/sFlit-1 might be a useful biomarker of placental vascular dysfunction and add its predictive value in identifying small foetuses accompanied by dysfunctional placenta

4. The cerebro-placental ratio (CPR) defined as the ratio between the pulsatility index measured in these arteries has been shown to be related to MRI abnormalities and abnormal neonatal neurobehavioral development. In fact, subtle opposite changes in flow patterns of umbilical arteries and middle cerebral ar-tery might also identify the fetus at risk.

5. Computerized CTG is of clinical relevance in identifying abnormal variability in severe growth re-stricted foetuses, yet short term variability and an exact identification of small and large accelerations might contribute to identify subtle changes in fetal adapta-tion to limited placental resources

6. Advanced analysis of fetal heart rate patterns specifically assessing changes in the autonomous regu-lation of fetal heart rate may also identify the IUGR fetus at increased risk. Early signs of hypoxemia are found in changes in the autonomous regulation of the fetal heart rate. This can be assessed by relatively new promising methods; spectral analysis or phase rectified signal averaging (PRSA) of the fetal heart rate, meas-ured by electromyography. Both methods are more specific than conventional analysis in identifying hy-poxemia during labour, or growth restriction ante par-

tum. Research from Munich, Utrecht, and from our group has shown abnormalities in about 30% of SGA foetuses, compared to only 5-8% with conventional computer analysis. Most of these cases were preterm and correlations with neonatal outcome have not yet been studied..

The challenge is to find combinations amongst these monitoring modalities that will identify and monitor late IUGR , in such a way that targeted inter-vention studies can be performed in order to optimize diagnosis and prevent long term cardiovascular and metabolic sequelae in this large subset of foetuses

Conclusions

It is clear from this brief analysis that late IUGR remains a major challenge in perinatal medicine. Un-fortunately the italian ultrasound screening protocol for IUGR at 30-32 weeks of gestation represents a major problem, too late for early severe IUGR, too early for late IUGR, a total useless misleading waste of money.

Whereas the TRUFFLE protocol represents a clear cut monitoring system for early IUGR , further studies are still to be performed in order to define the optimal screening and monitoring methods for late IUGR.

Reference

1. 2 year neurodevelopmental and intermediate perinatal out-comes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial.

2. Lees CC, Marlow N, van Wassenaer-Leemhuis A, Arabin B, Bilardo CM, Brezinka C, Calvert S, Derks JB, Diemert A, Duvekot JJ, Ferrazzi E, Frusca T, Ganzevoort W, Hecher K, Martinelli P, Ostermayer E, Papageorghiou AT, Schlembach D, Schneider KT, Thilaganathan B, Todros T, Valcamonico A, Visser GH, Wolf H; for the TRUFFLE study group. Lan-cet. 2015 Mar 4. pii: S0140-6736(14)62049-3.

Correspondance:Enrico Ferrazzi, MDDir. S.C. di Ostetricia e GinecologiaOspedale dei Bambini “V. Buzzi”ICP - Dip. di Scienze Cliniche - UNIMIE-mail: enrico.ferrazzi@icp.mi.it

LISA: Surfactant administration in spontaneous breathing. Which evidence from the literature?G. Lista, A. La Verde, F. CastoldiNICU «V. Buzzi» Ospedale dei Bambini, ICP, Milan, Italy

Summary. Recent human and animal studies demonstrated that surfactant can be delivered intratracheally without traditional intubation and bagging, but using a fine catheter inserted into the trachea of spontane-ously breathing preterm infants on CPAP. This strategy, known as LISA (less invasive surfactant adminis-tration) or MIST (minimal invasive surfactant therapy), seems to reduce failure of non-invasive respiratory approach. Avoiding mechanical ventilation and manual inflation it is possible to reduce lung injury due to baro-volutrauma. Moreover leaving the infants supported by N-CPAP during the maneuver, it is possible to reduce the risk of lung derecruitment. Further studies are needed to confirm the promising effects due to this strategy to deliver surfactant. (www.actabiomedica.it)

Key words: surfactant, spontaneous breathing, preterm infants, RDS

Acta Biomed 2015; Vol. 86, Supplement 1: 24-26 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

Surfactant administration is a well recognized management for respiratory distress syndrome (RDS) (1); N-CPAP and Non Invasive Ventilation (NIV) are often used to reduce the occurrence of mechanical ventilation (2-3) and so to minimize the risk of lung injury and the evolution towards bronchopulmonary dysplasia (BPD) .

INSURE procedure (transient intubation for surfactant administration, followed by a brief ventila-tion with final extubation to restore the non-invasive respiratory support in spontaneous breathing preterm infants) used in some recent RCTs (4-6), it has been recognized to reduce the need of mechanical ventila-tion (MV) (7).

Anyway in order to reduce the potential risk of tracheal intubation and lung injury due to the ventila-tion even if for a short period during INSURE pro-cedure, a new method to give exogenous surfactant without tracheal intubation and MV has been studied since 2001; this method leaves the baby spontaneously

breathing on CPAP during the procedure. The glottis is visualized with the laryngoscope and the surfactant is introduced in the trachea using different thin cath-eters. The procedure is called LISA (less invasive sur-factant administration) or MIST (minimal invasive surfactant therapy).

In literature many important experiences are de-scribed about the use of this “less or minimal” invasive modality for surfactant replacement therapy in spon-taneously breathing preterm infants on non-invasive respiratory support.

In Germany, Angela Kribs documented as a single center experience that this procedure is feasible with rare early complications and able to reduce the rate of N-CPAP failure ( from 46% to 25%) with an increased survival rate (from 76% to 90%) and survival without BPD (from 65% to 80%) (8-11)

After this single center experience, in Germany was planned the “AMV trial” (Avoiding Mechanical Ventilation): a RCT (19 NICUs) that enrolled 220 preterm infants (26.0-28.6 wks’GA) who were rand-omized to standard treatment (INSURE) or to inter-

Surfactant in spontaneous breathing: evidence from the literature 25

vention (LISA). Premedication was used at discretion of operator.

The LISA group showed significantly fewer me-dian days on mechanical ventilation, (0 days. IQR 0–3 vs 2 days, 0–5) and a lower need for oxygen supple-mentation at 28 days (30 infants [30%] vs 49 infants [45%], p=0·032) compared with the INSURE group. The thin catheter used (diameter 5 french) was always inserted with the Magill forceps. They recorded no differences between groups in terms of mortality (7 deaths in the intervention group vs 5 in the standard treatment group) and serious adverse events (21 vs 28 respectively) (12).

In 2014 using the data from the German Neona-tal Network (GNN) each infant (below 32 wks’GA) receiving LISA (between 2009 and 2012) was matched with one infant not treated with LISA. All the patients (1103 neonates in each group) were analyzed about their respiratory outcomes. LISA infants had lower rates of mechanical ventilation (41% versus 62%, p < 0.001), postnatal dexamethasone treatment (2.5% ver-sus 7%, p < 0.001), BPD (12% versus 18%, p = 0.001) and BPD or death (14% versus 21%, p < 0.001) than the controls.(13)

In Australia, Dargaville (14) planned a non-ran-domised feasibility study on two groups of spontane-ously breathing babies on N-CPAP (25-28 wks’ GA (n= 11) and 29-34 wks’GA (n=14) who received the “minimal invasive surfactant therapy” (MIST). With-out any premedication, a 5 F vascular catheter was inserted through the vocal cords under direct vision. Porcine surfactant (~100 mg/kg) was then instilled, followed by reinstitution of N-CPAP. The catheter was prepared by marking a point indicating the de-sired depth of insertion beyond the vocal cords with a marker pen (the point was different according to different GA). In all cases, surfactant was successfully administered (in 10-20 seconds) and N-CPAP re-established with reduction in FiO2 and pressure. An open feasibility study for the use of MIST was then organized (15), including stable preterm neonates (61 neonates of 25-32 wks’ GA) with a N-CPAP level above 7 cmH20 and need of FiO2 > 0.3-0.35 (ac-cording to GA). In this case the MIST procedure was given maintaining the infant with the CPAP prongs in situ and the administration of surfactant lasted about

15-30 seconds. Oxygenation improved rapidly after MIST procedure in all patients. Rates of pneumotho-rax, BPD and other major morbidities were not sub-stantially different between the MIST group and their respective controls managed with INSURE procedure. Duration of respiratory support was similar between MIST and control groups, but the lenght of oxygen therapy was lower in MIST group.

The last relevant clinical experience was published by a Turkish group that planned a RCT on preterm infants < 32 wks’GA. The infants in N-CPAP were randomized to receive surfactant (as a bolus in 30-60 seconds) while spontaneously breathing (using a 5F, flexible, sterile nasogastric tube for the procedure called TAKE CARE procedure) or with INSURE procedure (100 neonates per group). No sedation was used. Mean duration of both N-CPAP and MV were significantly shorter in the Take Care group (P values .006 and .002, respectively). BPD rate was significant-ly lower in Take Care group (relative risk –0.27, 95% confidence interval –0.1 to –0.72)(16).

The LISA procedure was tested in a spontaneous breathing preterm lamb model. Preterm lambs (n = 12) of 133–134 days of gestational age were randomized to receive : (i) continuous positive airway pressure (CPAP) only, (ii) CPAP + LISA, and (iii) intubation and me-chanical ventilation with surfactant administration. Surfactant was labeled with samarium oxide. During the next 180 min after randomization, blood gas analy-ses were performed. Postmortem, lungs were removed and surfactant distribution was assessed, and pressure–volume curves were performed. LISA improved oxy-genation, similar to conventional surfactant application techniques, despite lower surfactant deposition ( at the right upper lobe) and lung compliance. (17).

Conclusions

Surfactant administration to spontaneously breathing preterm infants (LISA or MIST procedure) seem to be safe, well tolerated and associated with re-duced NIV failure and less need of mechanical ventila-tion.

Actually there is not a universal consensus about the best choice of the catether to use for the procedure,

G. Lista, A. La Verde, F. Castoldi26

the lenght of manoeuvre, the need for Magill forceps and for an eventual pre-medication, the safety for all the spontaneously breathing preterm infants in non-invasive respiratory support, indipendently from the GA and birth weight, whenever the surfactant admin-istration is considered necessary.

Moreover it could be important to evaluate ( e.g. in animal experiment) if this procedure could be enhanced by a preliminary maneuver to recruit the lungs and so to allow a better distribution of surfactant in course of spontaneous breathing only supported by N-CPAP.

Anyway, even if BPD is a multifactorial disease, LISA/MIST procedure for surfactant administration because seems to improve short term respiratory out-comes (e.g. need of mechanical ventilation and lenght of respiratory support) could reduce the risk of lung injury and so the evolution towards BPD. More larger RCT are needed to confirm this hypothesis.

References

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

2. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very pre-term infants. N Engl J Med 2008; 358: 700-08.

3. Support Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010; 362: 1970-79.

4. Rojas MA, Lozano JM, Rojas MX, et al. Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009; 123: 137-42.

5. Sandri F, Plavka R, Ancora G, et al, for the CURPAP study group. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010; 125: e1402-09.

6. Dunn MS, Kaempf J, de Klerk R, et al. Randomized trial comparing 3 approaches to the initial respiratory manage-ment of preterm neonates. Pediatrics 2011; 128(5): e1069-76.

7. Stevens TP, Harrington EW, Blennow M, Soll R. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for pre-term infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev 2007; 4: CD003063.

8. Kribs A, Pillekamp F, Nseler CH,Vierzig A, Roth B. Early administration of surfactant in spontaneous breathing with nCPAP: feasibility and outcome in extremely premature in-fants (postmenstrual age <27 weeks). Pediatric Anesthesia 2007; 17: 364-9

9. Kribs A, Vierzig A, Hunseler C, et al. Early surfactant in spontaneously breathing with nCPAP in ELBW infants—a single centre four year experience. Acta Paediatr 2008; 97: 293-98.

10. Porath M, Korp L,Wendrich D,Dlugay V,Roth B, Kribs A. Surfactant in spontaneous breathing with nCPAP: neu-rodevelopmental outcome at early school age of infants < 27 weeks. Acta Paedaitrica 2011; 100: 352-359.

11. Meheler K, Grimme J, Abele J,Huenseler C, Roth B,Kribs A. Outcome of extremely low gestational age newborns af-ter introduction of a revised protocol to assist preterm in-fants in their transition to extrauterine life . Acta Paediatrica 2012; 101: 1232-1239.

12. Göpel W, Kribs A, Ziegler A, et al. Avoidance of me-chanical ventilation by surfactant treatment of spontane-ously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 2011; 378: 1627–34.

13. Gopel W, Kribs A, Hartel C, et al. Less invasive surfactant administration is associated with improved pulmonary out-comes in spontaneously breathing preterm infants. Acta Paediatrica 2015; 104: 241-246.

14. Dargaville PA, Aiyappan A, Cornelius A, et al. Preliminary evaluation of a new technique of minimally invasive sur-factant therapy. Arch Dis Child Fetal Neonatal Ed 2011; 96: F243-8.

15. Dargaville PA, Aiyappan A, De Paoli AG, et al. Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed 2013; 98: F122–F126.

16. Gozde Kanmaz H, Erdeve O, Emre Canpolat F, Mutlu B, Dilmen U. Randomized Controlled Trial Surfactant Ad-ministration via Thin Catheter During Spontaneous. Pedi-atrics 2013; 131: e502-e508

17. Niemarkt HJ, Kuypers E, Jellema R, et al. Effects of less-in-vasive surfactant administration on oxygenation, pulmonary surfactant distribution, and lung compliance in spontane-ously breathing preterm lambs. Pediatric Research 2014;76 (2): 166-170

Correspondance:Gianluca Lista, MDNICU - “V.Buzzi” Ospedale dei BambiniAzienda ICP, Milano-ItalyTel./Fax (39) (02) 57995346E-mail: g.lista@icp.mi.it

Hemodynamic management of the preterm infant with acute respiratory failure: role of the functional echocardiographyS. Mannarino1, G. Corana1, A. Zaroli1, A.C. Codazzi1, M. Pasotti1, R.M. Cerbo2, M. Stronati2

1 Pediatric Cardiology, Department of Pediatrics; 2 Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Summary. The functional echocardiography is a useful tool to evaluate the hemodynamic status of preterm infants, often needing a respiratory support during the first critical days of life. In NICU it can be helpful either for the clinical monitoring or the therapeutic management and the use of this technique can potentially improve short-term outcome of preterm infants. (www.actabiomedica.it)

Key words: functional echocardiography, hemodynamic status, preterm infants

Acta Biomed 2015; Vol. 86, Supplement 1: 27-31 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

The term “functional echocardiography” describes the use of echocardiography as an adjunct in the clini-cal assessment of the hemodynamic status in newborn infants. Usually pediatric cardiologists perform echo-cardiographic studies in the Neonatal Intensive Care Units (NICU) to diagnose or to monitor congenital heart diseases (CHD) and to screen for patent ductus arteriosus (PDA). However, neonatologists frequently have to deal with the management of hemodynami-cally instable preterm neonates and only a small pro-portion of these neonates may present an undiagnosed CHD in this setting (1-3).

The assessment of ventilated preterm infants with cardiovascular compromise is one of the main chal-lenges for neonatologists and, at present, continuous non-invasive real-time monitoring of cardiac function and hemodynamic status is not routinely available (4).

The cardiovascular compromise in these patients is the result of prenatal and postnatal factors that ad-versely affect organ perfusion during the period of

postnatal transition, especially in the presence of im-mature myocardium (5, 6).

Clinical signs of poor perfusion are useful but not sufficient to evaluate the cardiovascular status and there is a poor relationship between blood pressure (BP) and systemic blood flow (SBF), particularly in the context of highly variable systemic vascular resist-ances (SVRs) (7-9).

The functional echocardiography satisfies the need to obtain real-time information by a non-inva-sive and easily reproducible method that can provide data useful for the clinical decision-making. This tech-nique, performed by adequately trained intensivists, can change the clinical management and potentially improves short-term outcome (3, 10, 11). At present no data exist on long-term outcome.

In order to get reliable echocardiographic pa-rameters it is necessary to repeat measurements using more than one method, to minimize inter- and intra-observer variability, to achieve good quality of images also in the presence of hyperinflated lungs in ventilated preterm infants.

S. Mannarino, G. Corana, A. Zaroli, et al.28

Hemodynamic compromise

Prematurity increases the need for invasive and non-invasive respiratory support and infants with se-vere respiratory distress syndrome (RDS) may have lower BP than infants with less severe or without RDS (12, 13). Different factors, often acting together, influ-ence the relationship between BP and SBF:

1) The increased airway pressure depending on the type of invasive ventilation (conventional or high frequency ventilation) and the use of positive-pressure ventilation influence SBF. Many authors report a negative correlation be-tween the mean airway pressure in mechanical ventilated preterm infants and the BP. High ventilation pressures can reduce the preload by reducing systemic and/or pulmonary venous return, while direct compression of cardiac chambers increases the afterload and reduces the stroke volume. So mechanical ventilation alters intrathoracic pressure and thereby affects the cardiovascular system, mainly the right ventricle (RV); however, considering an in-series circulation, a reduction of the RV output also reduces that of the left ventricle (LV) (14, 15, 16). In addition, a too high positive end-expiratory pressure (PEEP) and, presumably, the resultant hyperinflation of the lungs may induce the release of plasmatic factors having negative inotropic action (17). Current data show a decreased necessity of mechanical ven-tilation by using early nasal continuous positive airway pressure (nCPAP) with early surfactant administration. The INSURE method (Intu-bation - Surfactant - Extubation) followed by positioning nCPAP potentially can reduce the incidence of hypotension and decreased perfu-sion in very low birth weight (VLBW) infants (18).

2) Blood losses may further reduce the preload; a delayed cord clamping (DCC) reduces the risk of hypovolemia (19).

3) There is a close relationship between SVRs and cardiac output; different factors affect SVRs such as carbon dioxide level, unbalance of vas-oactive substances, inadequate immature sym-

pathoadrenal system and sepsis. Furthermore, during the first hours of life (very vulnerable status) the enhanced SVRs can significantly decrease SBF with consequent poor neonatal outcome (20, 21).

4) PDA, which exposes LV to the combined pul-monary and systemic vascular resistances, plays an important role in determining hemodynam-ic instability when it is significant (22, 23).

5) The role of myocardial dysfunction as a pri-mary cause of hypotension in severely asphyxi-ated preterm infants is well-documented (24). Transient dysfunction is usually the result of an unsatisfactory response of immature myocar-dium to the suddenly increased left afterload and can play a role in the development of a low flow in the superior vena cava (SVC) (25).

Functional echocardiography

The functional echocardiography allows the evaluation of different useful parameters: blood flow measurements; measurements of myocardial perfor-mance, ductal and atrial shunting, pulmonary artery pressure (PAP). The complex relationship among these parameters in the unique condition of the transitional circulation implies a complete evaluation of all these measurements for the correct assessment of the pre-term infants’ hemodynamic status.

• Blood flow measurements Three main measures are necessary to estimate stroke volume: mean flow velocity, cross-sec-tional vessel area and heart rate. To minimize measurement errors, the flow must be laminar and sampled at an angle < 20° while the vessel diameter must be achieved when the ultrasound beam hits the vessel at 90°. It is important to consider that the LV output can be used to es-timate SBF only in the absence of ductal shunt, otherwise it becomes an index of pulmonary blood flow as the sum of the SBF and the left to right shunt across the duct. In this situation, the RV output is a better measure of the SBF. There is a good correlation between RV and LV out-

Hemodynamic management of the preterm infant with acute respiratory failure 29

put in the absence of atrial and ductal shunts, but a large left to right shunt overestimates RV output (4). The SVC flow is independent of shunts and represents the portion of SBF for the brain and the upper body. Its measurements is technically difficult and in newborns breath-ing spontaneously requires to average from 10 cardiac cycles (4). A low SVC flow relates to a poor neurological outcome (26).

• Measurements of myocardial performance The simplest measure of the LV systolic func-tion is the fractional shortening (FS), commonly derived from a M-mode study. Unfortunately, during transitional circulation, the individual fall time of pulmonary vascular resistances (PVRs) and the close interdependence of the two ven-tricles affect the septal and LV anterior wall mo-tion, making the FS a not very reliable measure. Other methods to evaluate myocardial perfor-mance have been suggested (4, 27). An impor-tant limit of the estimation of the global systolic function is the impossibility to differentiate how each of the three major components (preload, afterload and intrinsic contractility) affects the changes. The estimation of the velocity of cir-cumferential fiber shortening (VCF) and the relationship between VCF and wall stress (WS) (28) are helpful, but not so easy to be performed in clinical practice. In future, the functional study of the immature heart with the tissue Doppler technique could provide many advantages.

• PDA The echocardiographic assessment of PDA in-cludes different parameters: ductal diameter, transductal flow pattern, mean left pulmonary artery (LPA) velocity, signs of left heart volume and pressure overload (LA/Ao ratio, mitral re-gurgitation jet, E/A ratio, isovolumic relaxation time IVRT), arterial diastolic reverse flow in the normal end-organ vessels (cerebral, mesenteric, and renal arteries). The risk of hemodynamically significant PDA increases with low gestational age and, although it has been linked to impor-tant neonatal morbidities (early pulmonary hemorrhage, chronic lung disease and neonatal necrotizing enterocolitis), there is little evidence

that its treatment improves either short-term or long-term outcomes (22, 23, 29). However, echocardiographic criteria such as ductal inter-nal diameter greater than 1.5 mm, LA/Ao great-er than 1.5, absent or retrograde diastolic flow in postductal descending aorta, increased mean LPA velocity, in association with demonstrated adverse clinical effects, address to PDA closure (30, 31).

• Atrial shunting In preterm babies left-to-right atrial shunt can be both significant and quite persistent; atrial shunting is determined predominantly by RV filling or diastolic pressure. It can contribute to increase pulmonary blood flow and over-estimates the SBF in the presence of PDA. A bidirectional shunt alone is not a marker of pul-monary hypertension; an exclusive right-to-left atrial shunting is rare and should be investigate for CHD (4).

• PAP PAP echocardiographic estimation is obtained by measuring tricuspid regurgitation jet or ductal shunt and the direction of atrial shunt (4). When pulmonary hypertension (usually a problem of term or near term newborn) af-fects preterm neonates, excluding a CHD or a secondary cause such as pulmonary embolism is mandatory.

Conclusions

Currently there is agreement to perform an echocar-diography during the first 12 hours of life in extremely low- gestational-age (ELGA) infants and in the preterm neonates born after 27 weeks of GA with respiratory compromise, to monitor the vulnerable transition pe-riod. This evaluation must include:

a) the measurement of SBF with a simple method: if atrial shunt is not very large, maximum velocity in the main pulmonary artery (MPA) greater than 0.45 m/sec most likely excludes low SBF; on the contrary, when maximum velocity in MPA is lower than <0.45 m/sec, it is necessary to estimate the RV output and to evaluate the SVC flow (32);

S. Mannarino, G. Corana, A. Zaroli, et al.30

b) the ductus arteriosus assessment: early con-striction or patency, considering that significant left to right shunt is often clinically silent during the first hours or days of life.

Further echocardiographic assessments are neces-sary when there is the suspicion of a circulatory com-promise or, longitudinally, to follow the effectiveness of some therapeutic decisions. A full assessment of ductal patency, the measurement of LV and RV output and the indirect (visual) and/or direct (FS, VCF, tissue doppler) measurement of the myocardial function can better address clinical decision.

References

1. Kluckow M, Seri I, Evans N. Functional echocardiography: an emerging clinical tool for the neonatologist. J Pediatr 2007; 150: 125-30.

2. Kluckow M, Seri I, Evans N. Echocardiography and the neonatologist. Pediatr Cardiol 2008; 29: 1043-47.

3. Sehgal A, McNamara PJ. Does point-of-care functional echocardiography enhance cardiovascular care in the NICU? J Perinatol 2008; 28: 729-35.

4. Evans N. Functional echocardiography in the Neonatal In-tensive Care Unit. In Kleinman CS, Seri I: Hemodynamics and cardiology: neonatology questions and controversies. Philadelphia: Elsevier Saunders, 2012: 95-123.

5. Rudolph AM. Circulation in the normal fetus and cardio-vascular adaptations to birth. In Yagel S, Silverman NH, Gembruch U: Fetal cardiology. New York: Informa Health-care, 2008: 131-52.

6. Evans NJ, Archer LNJ. Postnatal circulatory adaptation in term and healthy preterm neonates. Arch Dis Child 1990; 65: 24-26.

7. Evans NJ. Assessment and support of the preterm circula-tion. Early Hum Dev 2006; 82: 803-10.

8. Dempsey EM, Al Hazzani F, Barrington KJ. Permissive hypotension in the extremely low birth weight infant with signs of good perfusion. Arch Dis Child Fetal Neonatal Ed 2009; 94: F241-44.

9. Conway-Orgel M. Management of hypotension in the very low-birth-weight infant during the golden hour. Adv Neo-natal Care 2010; 10: 241-45.

10. El-Khuffash AF, McNamara PJ. Neonatologist-performed functional echocardiography in the neonatal intensive care unit. Semin Fetal Neonatal Med 2011; 16: 50-60.

11. Mertens L, Seri I, Marek J, et al. Writing group of the American Society of Echocardiography (ASE) in collabo-ration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardi-ologists (AEPC). Targeted Neonatal Echocardiography in the Neonatal Intensive Care Unit: Practice Guidelines and

Recommendations for Training. J Am Soc Echocardiogr 2011; 24: 1057-78.

12. van Bel F, Latour V, Vreman HJ, et al. Is carbon monox-ide-mediated cyclic guanosine monophosphate production responsible for low blood pressure in neonatal respiratory distress syndrome? J Appl Physiol 2005; 98:1044-49.

13. Korvenranta H, Kero P, Valimaki I. Cardiovascular moni-toring in infants with respiratory distress syndrome. Biol Neonate 1983; 44:138-45.

14. Kluckow M, Evans N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. J Pediatr 1996; 129: 506-12.

15. Evans N, Kluckow M. Early determinants of right and left ventricular output in ventilated preterm infants. Arch Dis Child 1996; 74: F88-94.

16. Skinner JR, Boys RJ, Hunter S, Hey EN. Pulmonary and systemic arterial pressure in hyaline membrane disease. Arch Dis Child 1992; 67: 366-73.

17. Smeding L, Lust E, Plötz FB, Groeneveld AB. Clinical im-plications of heart-lung interactions. Neth J Med 2010; 68: 56-61.

18. Lakkundi A, Wright I, de Waa K. Transitional hemody-namics in preterm infants with a respiratory management strategy directed at avoidance of mechanical ventilation. Early Hum Dev 2014; 90: 409-12.

19. Yigit MB, Kowalski WJ, Hutchon DJ, Pekkan K. Transi-tion from fetal to neonatal circulation: Modeling the effect of umbilical cord clamping. J Biomech 2015, http://dx.doi.org/10.1016/j.jbiomech.2015.02.040i.

20. Noori S, Stavroudis TA, Seri I. Systemic and cerebral hemo-dynamics during the transitional period after premature birth. Clin Perinatol 2009; 36: 723-36.

21. Kluckow M. Low systemic blood flow and pathophysiol-ogy of the preterm transitional circulation. Early Hum Dev 2005; 81: 429-37.

22. Kitterman JA, Edmunds LH Jr, Gregory GA, Heymann MA, Tooley WH, Rudolph AM. Patent ducts arteriosus in premature infants. Incidence, relation to pulmonary disease and management. New Eng J Med 1972; 287: 473-77.

23. Kluckow M, Evans N. Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr 2000; 137: 68-72.

24. Cabal LA, Devaskar U, Siassi B, Hodgman JE, Emman-ouilides G. Cardiogenic shock associated with perinatal as-phyxia in preterm infants. J Pediatr 1980; 96: 705-10.

25. Osborn DA, Evans N, Kluckow M. Left ventricular con-tractility in extremely premature infants in the first day and response to inotropes. Pediatr Res 2007; 61: 335-40.

26. Hunt R, Evans M, Rieger I, Kluckow M. Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. J Pediatr 2004; 145: 588-92.

27. Lee LA, Kimball TR, Daniels SR, Khoury P, Meyer RA. Left ventricular mechanics in the preterm infant and their effect on the measurement of cardiac performance. J Pediatr 1992; 120: 114-19.

28. Rowland DG, Gutgesell HP. Noninvasive assessment of

Hemodynamic management of the preterm infant with acute respiratory failure 31

myocardial contractility, preload, and afterload in healthy newborn infants. Am J Cardiol 1995; 75: 818-21.

29. Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus Arch Dis Child Fetal Neonatal Ed 2014; 99: F99-104.

30. Heuchan AM, Clyman RI. Managing the patent ductus ar-teriosus: current treatment options. Arch Dis Child Fetal Neonatal Ed 2014; 99: F431-36.

31. Sehgal A, Paul E, Menahem S. Functional echocardiogra-phy in staging for ductal disease severity: role in predicting outcomes. Eur J Pediatr 2013; 172: 179-84.

32. Evans N. Support of the preterm circulation: keynote ad-dress to the Fifth Evidence vs Experience Conference, Chi-cago, June 2008. J Perinatol 2009; 29: S50-57.

Correspondance:Mannarino SavinaPediatric Cardiology, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi 19, 27100 Pavia, ItalyTel. + 39 0382 502915E-mail: savinamannarino@smatteo.pv.it

Caffeine for preterm infants: current indications and uncertaintiesS. Nobile, V.P. CarnielliNeonatology Unit, Salesi Children’s Hospital, Ancona (Italy)

Summary. Caffeine is one of the most commonly used therapies in Neonatology, with different indications such as the treatment of apnea and the prevention of extubation failure and bronchopulmonary dysplasia. However, there are still uncertainties regarding effects on central nervous system development, time of dis-continuation and dosing of the drug. (www.actabiomedica.it)

Key words: caffeine, preterm infant, apnea, bronchopulmonary dysplasia

Acta Biomed 2015; Vol. 86, Supplement 1: 00-00 © Mattioli 1885

O r i g i n a l a r t i c l e

Background

Caffeine is one of the most commonly used thera-pies in Neonatology, with different indications such as the prevention/treatment of apnea and the prevention of extubation failure.(1,2) Recent studies showed that caffeine is also effective in reducing bronchopulmo-nary dysplasia(BPD) rates (3-7).

Nearly all very low birth weight infants (VLBWi; <1,500 g) experience apnea due to brainstem and pe-ripheral chemoreceptor immaturity; in addition, path-ologic conditions such as sepsis, respiratory failure, intracranial hemorrhage, and seizures may increase the number and severity of apnea events (3).

BPD is another common complication of prema-turity, which occurs in over 40% of VLBWi. Neonates with BPD are at high risk of long-term lung disease, adverse neurodevelopmental outcomes and hospitali-zation in the first year of life. Few safe and effective therapies are available to prevent the disease, including caffeine (4).

Mehods

We performed a literature search on Pubmed and selected the most relevant studies about pharmacology and clinical use of caffeine among preterm infants.

Results

Pharmacology

Caffeine is a methylxanthine acting as a non-specific inhibitor of 2 (A1 and A2a) of the 4 known adenosine receptors A1, A2a, A2b and A3. Adenosine is a purine nucleoside produced in human tissues, in-cluding the brain, whose levels increase rapidly with inflammation (1). Adenosine preserves brain ATP lev-els and protects brain cells from energy failure and cell death during experimental hypoxia and ischemia in a variety of animal models.

Caffeine is thought to act by increasing cen-tral respiratory drive and by lowering the threshold of response to hypercarbia, as well as by stimulating diaphragmatic contractility and preventing diaphrag-matic fatigue. Other suggested mechanisms include diuretic effect, increased cardiac output and blood pressure, improvement in overall pulmonary mechan-ics, resulting in a reduction of endotracheal ventilation and protection against associated lung injury (8).

Most studies reported intravenous administra-tion of caffeine. The systemic absorption of caffeine from the gastrointestinal tract has been found to be complete in preterm infants (9). Therefore, caffeine administration can be simplified because dosing can

Caffeine for preterm infants 33

be switched between orogastric and intravenous routes as required. The mean absorption half-life is about 30 minutes.

Caffeine is very rapidly distributed, with a half-life of < l0 minutes. Caffeine clearance has been described as a function of body weight and postnatal age (which is in turn correlated with renal and hepatic develop-ment). Preterm infants tolerate caffeine very well, even at serum concentrations of 70 mg/L or above. Lee et al reported a very long caffeine half-life of 86 to 277 hours, much higher compared with 5 hours in adults (8). The large majority of the drug is cleared by the kidneys. Distribution reflects a partitioning of caffeine into the relatively larger extracellular fluid volume of the newborn, especially in skeletal muscle.

The binding to serum albumin is low (35%) for caffeine concentrations up to 20 mg/L. Indeed, it is likely that the protein binding of caffeine in premature neonates is linear to at least 70 mg/L, as pointed out by Lee and colleagues (8).

Natarajan et al. 2007 suggested that routine mon-itoring of plasma concentrations of caffeine is unnec-essary, even in VLBWi with renal or hepatic dysfunc-tion or after prolonged use, because the vast majority of patients achieve blood concentrations in the range of 5 to 20 mg/L (10). In the subgroup of infants who do not show a clinical response to standard doses of caffeine, higher plasma levels may be targeted, and monitoring of plasma levels may be prudent. Pharma-cokinetic studies in premature neonates showed that the half-life of caffeine is prolonged to 102.9 ± 17.9 hours and remains prolonged for as long as 38 weeks’ gestation. The transition to adult levels of elimina-tion occurs at 3 to 41⁄2 months. Other factors such as cholestasis and breastfeeding seem to further prolong the half-life of caffeine.

The recommended standard dosing for caffeine citrate is 20 to 40 mg/kg (loading dose) followed by 5 to 8 mg/kg per day as maintenance. Larger mainte-nance doses up to 20 mg/kg day in the periextubation period have shown higher rates of successful extuba-tion, without adverse events in the first year of life (2).

Reported adverse events during caffeine therapy are tachycardia, central stimulation, and alimentary tract toxicity; however, caffeine is a relatively safe drug, and even at the maximum observed concentration of

approximately 80 mg/L, it has few significant acute adverse effects in preterm infants, and no apparent detrimental developmental outcomes up to at least 1 year of age after administration during the periextuba-tion period (2).

There is uncertainty on the precise desired plas-ma concentration and its correlation with efficacy, as clinically effective plasma concentrations vary over a wide range of 5 to 50 mg/L. Although a decrease in apnea and increase in respiratory drive is known at plasma concentrations as low as 2.9 and 4 mg/L, optimal effect is at 10 mg/L. Higher doses and caf-feine levels have been targeted with some benefit and no adverse effects. However, a recent study showed that administering intravenous loading dose 80 mg/kg compared to 20 mg/kg in the first 24 hours of life was associated with higher incidence of cerebellar in-jury with subsequent alterations in early motor per-formance (11).

Clinical studies

Caffine has been increasingly used from the 70’s to treat apnea, prevent extubation failure and BPD. Given the concerns for potential adverse events that emerged from in vitro studies (brain toxicity in hypox-ia models), large trials have been conducted in order to evaluate short- and long-term safety and efficacy of caffeine (3,12,13).

The CAP trial, an international, multicenter, pla-cebo-controlled randomized trial conducted on pre-term infants (with birth weight below 1250 grams) showed that caffeine significantly reduced the fre-quency of BPD (36.3 vs 46.9% for placebo). The rates of death before the first discharge home, ultrasono-graphic signs of brain injury, and necrotizing enter-ocolitis did not differ significantly between the two groups (3).

Other studies confirmed the decreased neonatal morbidity (in terms of death, BPD, PDA, duration of endotracheal intubation) with early (before 3 days of life) versus late initiation of therapy (4-7).

In a later follow-up study from the CAP tri-al,(12) caffeine compared to placebo significantly improved the rate of survival without neurodevel-opmental disability at a corrected age of 18 to 21

S. Nobile, V.P. Carnielli34

months (59.8% vs. 53.8%, odds ratio 0.77; 95% con-fidence interval 0.64 to 0.93; P = 0.008). There was no significant difference between the two groups in the rate of death before the age of 18 months. The rates of deafness and bilateral blindness were low and likewise not significantly different between the two groups. Treatment with caffeine as compared with placebo significantly reduced the incidence of cer-ebral palsy (4.4% vs. 7.3%; odds ratio 0.58; 95% CI 0.39 to 0.87; P = 0.009) and of cognitive delay (33.8% vs. 38.3%; odds ratio 0.81; 95% CI 0.66 to 0.99; P = 0.04). Nearly one-half of the neuroprotective ef-fect of caffeine at 18 months could be explained by the earlier discontinuation of positive airway pressure in infants assigned to caffeine. Another possibility is that caffeine has antioxidant capacity, as suggested by a recent experimental study on mice reporting that caffeine exerts protection for neonatal neurons ex-posed to high oxygen (14).

In a subsequent follow-up study of the CAP tri-al in which infants were evaluated at 5 years of age, Schmidt et al. reported that there was no difference between children treated with caffeine and those who received placebo with regard to a combined outcome of death or survival with 1 or more of the following: motor impairment, cognitive impairment, behavioral problems, poor general health, severe hearing loss and bilateral blindness (13).

Regarding the optimal time of discontinuation of caffeine therapy, a recent study pointed out that ex-tending caffeine treatment to 40 weeks’ post-menstru-al age decreases intermittent hypoxia events (SatO2 <90%) compared to earlier discontinuation (34 to 37 weeks PMA); thus, prolonged administration might improve neurodevelopmental outcome among preterm infants (15).

Discussion

Caffeine appears to be a safe and effective therapy for apnea of prematurity, prevention of BPD and ex-tubation failure in preterm infants (i.e.born <29 weeks’ gestational age) who require ventilatory support or present apnea events. More clinical research is needed to confirm potential neuroprotective properties of the

drug and to clarify the optimal dosing and time to dis-continuation of therapy.

References

1. Kreutzer K, Bassler D. Caffeine for Apnea of Prematurity: A Neonatal Success Story. Neonatology 2014; 105: 332- 336.

2. Steer P, Flenady V, Shearman A, Charles B, Gray PH, Henderson-Smart D, et al. High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2004; 89: F499-F503.

3. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine Therapy for Apnea of Prematu-rity. N Engl J Med 2006; 354: 2112-21.

4. Patel RM, Leong T, Carlton DP, Vyas-Read S. Early caf-feine therapy and clinical outcomes in extremely preterm infants. Journal of Perinatology 2013; 33: 134-140.

5. Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, et al. Caffeine for Apnea of Prematurity Trial: benefits may vary in subgroups. J Pediatr 2010; 156: 382-387.

6. Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr 2015; 169: 33-8.

7. Dobson NR, Patel RM, Smith PB, Kuehn DR, Clark J, Vyas-Read S, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr 2014; 164:9 92-998.

8. Lee TC, Charles B, Steer P, Flenady V, Shearman A. Popu-lation pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther 1997; 61: 628-40.

9. Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A. Caffeine Citrate Treatment for Extremely Pre-mature Infants With Apnea: Population Pharmacokinetics, Absolute Bioavailability, and Implications for Therapeutic Drug Monitoring. Ther Drug Monit 2008; 30: 709-716.

10. Natarajan G, Botica ML, Thomas R, Aranda JV. Therapeu-tic Drug Monitoring for Caffeine in Preterm Neonates: An Unnecessary Exercise? Pediatrics 2007; 119; 936-940.

11. McPherson C, Neil JJ, Tjoeng TH, Pineda R, Inder TE. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res 2015; doi: 10.1038/pr.2015.72.

12. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. N Engl J Med 2007; 357: 1893-1902.

13. Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematu-rity. JAMA 2012; 307: 275-282.

14. Endesfelder S, Zaak I, Weichelt U, Bührer C, Schmitz T.

Caffeine for preterm infants 35

Caffeine protects neuronal cells against injury caused by hy-peroxia in the immature brain. Free Radic Biol Med 2014; 67: 221-34.

15. Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, et al. Effects of Caffeine on Intermittent Hy-poxia in Infants Born Prematurely-A Randomized Clinical Trial. JAMA Pediatr 2014; 168: 250-257.

Correspondance:Stefano Nobile, MDNeonatology UnitSalesi Children’s HospitalAncona, ItalyE-mail: stefano.nobile@ospedaliriuniti.marche.it

Late preterm babies and the risk of neurological damageLuca A. RamenghiNeonatal Intensive Care Unit, Istituto Giannina Gaslini IRCCS, Genova, Italy

Summary. Late preterm infants (born be tween 34+0 and 36+6 weeks gestation) account for the recent striking increase in premature birth and they carry a higher vulnerability to suffer brain insults compared to term in-fants. These babies can develop any kind of known brain lesions including those affecting the most premature babies (i.e.an in traventricular haemorrhage) and lesions affecting more typically term babies like asphyxia and stroke. In other words there is not a specific brain lesion characterizing this gestational age group, and there is not a specific maturational landmark although “subplate neurons” are suppose to ultimate their connectivity in this period and the cortical volume is significantly increasing. In addition we should not forget the possibility that “late preterm babies” may present neu rological clinical impairments in the absence of rec ognized mor-phological brain lesions even with the use of highly sophisticated MR imaging techniques. For these reasons a wider use of more sophisticated neuro radiological studies is not sufficient to better understand why some studies highlight that the risk of developmental delay or disability can reach 36% higher among late preterm infants compared with term infants. We believe we should improve also our skills to identify even those very subtle clinical signs of impairment deserving further investigations although we often admit these babies in the normal post natal nurseries where clinical observation cannot be so appropriate. (www.actabiomedica.it)

Key words: late preterm, neonatal brain, preterm brain

Acta Biomed 2015; Vol. 86, Supplement 1: 36-40 © Mattioli 1885

O r i g i n a l a r t i c l e

Introduction

Late preterm infants (defined as babies born be-tween 34+0 and 36+6 weeks gestation) have been grouped together only because they are the most represented premature infants (about 72% of preterm births) in the developed countries, reaching 7-8% of total live-births, and they account for the striking increase in premature birth which occurred in the last two decades (1). There is not a peculiar common pathway to develop certain disease characterizing this peculiar gestational age group, especially for cerebral lesions as between 34 and 36 weeks of gestation there is a continuum between the most important prematurity and what we intend for term babies.

The higher vulnerability of late preterm infants to develop diseases in the early neonatal period, compared to term babies, is well known. Mortality rate shows a 3-fold increase compared to term born controls and

morbidity rates approximately doubles for each ad-ditional gestational week earlier than 38 weeks (1). Short term morbidities of late preterm infants include temperature instability, respiratory distress syndrome, excessive weight loss and dehydration requiring intra-venous infusion, sepsis, hypoglycemia and jaundice re-quiring phototherapy (2).

Cerebral Magnetic Resonance Imaging (MRI) studies have documented morphological maturational processes such as myelination, cortical folding and pro-gressive involution of germinal matrix (3,4), together with changes in specific functions like visual perfor-mances (5,6). There is not another gestational age so arbitrary gathered as there is not a specific landmark of an achieved maturation but only an amalgam of disap-pearing processes (i.e., involution of the germinal ma-trix) and maturing one (i.e., myelination) (3,4). One of most characteristic developmental neurological pro-cess of this period is perhaps the ultimate maturation

Late preterm babies and the risk of neurological damage 37

of “subplate neurons” making neuronal connections although cannot be associated to any specific brain le-sion in case this process is altered (7).

Cortical volume in the late preterm infant is only 53% of the term volume, with approximately half the volume being attained in the last 6 weeks of gesta-tion. In addition, myelinated white matter is present in minimal quantities in an extremely preterm infant, but increases dramatically as term approaches, with a 5-fold volume increase between 35 and 41 weeks (8). Vulnerability of specific neuronal populations in the late preterm is due to multiple factors but, like white matter vulnerability in the early-preterm brain, exci-totoxicity and oxidative stress may play a significant role in late-preterm injury. For example, at that stage there is an over-expression of glutamate receptors in regions like the basal ganglia (9). Those receptors are necessary for long-term potentiation and connectiv-ity, but after an insult, their activity can lead to the production of nitrogen and oxygen free radicals that can injure nearby cells. Basal ganglia and thalami are also recognized as metabolically active zones with in-creased energy requirements which contribute to their particular vulnerability to acute hypoxic insults.

For these reasons late preterm babies are exposed to a wider spectrum of brain lesions common to both most premature and more mature babies as they can develop not only germinal matrix-intraventricular haemorrhage (GMH-IVH) and cystic periventricu-lar leukomalacia (cPVL) (10) but also arterial/venous stroke (11,12), hypoxic-ischemic encephalopathy (HIE) (13), and those parenchymal injuries following hypoglycaemia. The adding problem is the paucity of the related clinical symptoms compared to more term babies therefore these lesions can remain undiagnosed until later in childhood, and may contribute to explain the increased risk of impaired neurobehavioral out-come reported in the literature.

The wide range of cerebral lesions affecting “late preterm babies”

The peculiar contradiction of the highly unspe-cific brain vulnerability of babies born between 34 and 36 weeks + 6 days make possible for these babies

to develop any kind of known brain lesions including those affecting the most premature babies (i.e.an in-traventricular haemorrhage) and lesions affecting more typically term babies like asphyxia and stroke (14). In addition, you can have a variable number of different cerebral lesions affecting the same baby at the same time. A very indicative lesion of this multipotential brain vulnerability is showed in case of venous throm-bosis (15). A very late appearance of a mild intraven-tricular haemorrhage together with periventricular white matter changes is very suspsicious for a venous thrombosis of the deep venous system. At 34 wks’GA is still possible to have an intraventricular bleed from the remaining germinal matrix at the caudo-thalami notch and white matter bilateral lesions due to in-volvement of the medullary veins mimicking a PVL lesions (15,16,17). This process can be triggered by the increased venous pressure occuring during throm-bosis of the deep venous system (i.e, internal cerebral vein,vein of galen or straight sinus) (15,16).

Periventricular leukomalacia

Although the incidence of the most severe cystic forms of PVL has dramatically decreased in very low birth weight babies it is our impression that some un-expected and clinically very subtle forms of PVL are still possible in less premature, like the “late preterm babies”. We believe these are those forms potentially linked to chorioamnionitis, a condition very likely to have been over emphasized in the pathogenesis of the almost disappeared PVL (10). Other milder form of PVL, usually referred to as ‘‘punctate lesions’’, pre-dominately linearly organized and bordering the lat-eral ventricles are likely to be present in late preterm babies although good epidemiological studies are lack-ing in this field (18).

Arterial stroke

In most cases, like for arterial stroke affecting term babies, arterial stroke results from placental em-boli passing through the patent foramen ovale into the aorta, where the branching of the left common carotid

L.A. Ramenghi38

offers the easiest anatomical path. The left middle cer-ebral artery, in fact, is the most commonly involved vessel. Injury usually involves both the white matter and the cortex, with the posterior white matter being involved more frequently than the anterior regions (11,12,19). These injuries also affect the brain of pre-mature babies of gestational age above 32 weeks with a similar pattern of lesions involving major branches of arteries, while involvement of the smaller lenticulo-striate branches seems to be more common in preterm infants with GA of 28–32 weeks. It remains difficult to identify a specific pathogenesis for arterial infarctions in the minor arterial branches. These younger babies are most often the ones receiving intensive care, and small air bubbles which might pass through the heart via the foramen ovale after insertion of an umbilical ve-nous catheter have been reported as a potential patho-genetic mechanism (19). However, only twin-to-twin transfusion syndrome, foetal heart rate abnormality and hypoglycaemia have been found to be significant and independent risk factors for developing arterial infarctions in the entire population of preterm babies (20,21). No maternal risk factors have been identified. With regard to neurodevelopmental outcome, infants with a main branch arterial infarction are at greater risk of motor/cognitive impairment compared to those with lenticulostriate branches. Preterm compared to term babies have more language problems at 2 years of post-conceptional age (20,21).

Asphyxia

Studies of hypoxic-ischaemic encephalopathy (HIE) in late preterm infants demonstrate that in this category hypoxic insult mainly affects the grey matter, but the sites may differ compared to the more mature term brain. Basal ganglia are most frequently involved, particularly the ventro-lateral thalami and posterior putamen, as occurs in term babies (13). Late preterm infants are more likely to show brainstem lesions com-pared to term infants, indicating an increased sus-ceptibility of the brain stem at these slightly younger gestational ages. Less frequently, injury may also oc-cur to the hippocampus, the cerebral cortex and the subcortical white matter, particularly the perirolandic

region. It is interesting to note that the late preterm in-fant does not often show cortical abnormalities around the central sulcus, which is, on the contrary, a frequent finding in-term infants. It is likely that this region be-comes more vulnerable at term due to its active my-elination during the very last weeks of gestation (13). This observation confirms that the metabolic demands of myelination may compound the increased vulner-ability of cortical neurons and brainstem, respectively, at more and less mature gestational ages. Ischaemic le-sions of the basal ganglia and thalami are associated with cerebral palsy and cognitive impairment. In the case of a severe insult, these lesions can be accompa-nied by abnormalities in specific cortical regions and in the adjacent subcortical white matter, exacerbating the cognitive deficit. Coexisting abnormal MRI signal intensity in the posterior limb of the internal capsule is a powerful predictor of motor outcome severity (13).

Cerebral palsy in late preterm and intrauterine growth retardation

Two thirds of cerebral palsy arises in the 97% of singletons born at or after 35 weeks of gestation (22). The current impression is that the prevalence of cer-ebral palsy in these relatively mature neonates, unlike that of survivors of very preterm birth, has not fallen in recent decades. In very recent and convincing stud-ies in which the contribution of potentially asphyxial birth events, inflammation, fetal growth restriction, and birth defects recognized by age 6 years to each of these outcomes was evaluated it emerged that foetal growth restriction and birth defects recognized by age 6 years were more substantial contributors to cerebral palsy and neonatal death than potentially asphyxial birth events and inflammation (22).

The long-term neurological impairment frequent-ly seen in children who showed intrauterine growth re-tardation (IUGR) cannot be attributed to the presence of overt brain lesions (23). Conventional MR imaging has failed to show even more subtle lesions in IUGR babies, while the number of DTI studies are booming in the search for a common pattern of developmen-tal abnormality. Whatever sophisticated neurological techniques may be used to study brain development,

Late preterm babies and the risk of neurological damage 39

the risk of brain damage in IUGR neonates could re-flect both the liabilities of intrauterine compromise and, in minor entity, the penalties of prematurity. In addition, the exact pathogenetic meaning of ‘‘brain sparing’’, which is not always a guarantee of the full protection of brain development during intrauterine life, needs to be better understood, as in our experience this was associated to an impairment of myelination (24).

Conclusion

An exact knowledge of the specific contribution of each risk factor for brain vulnerability of late pre-term babies is far from being understood as large stud-ies with epidemiological insights are very difficult to be performed. It is likely that gestational ages at birth with occurrence of neonatal comorbidities are the most important risk factors for detecting brain lesions in late preterm population especially in those born at 34 weeks more than at 36 weeks of gestation (25).

In addition to difficulties in diagnosing minor brain lesions and correlating these to specific minor neurological impairment we should not forget the possibility that “late preterm babies” may present neu-rological clinical impairments in the absence of rec-ognized morphological lesions even with use of MRI imaging (25). The problem is further compounded by the fact that we are less aware of the pathogenetic mechanisms causing neurological impairments in late preterm babies since we can only postulate the likely areas of vulnerability that would seem to be subcorti-cally located, and that particularly affect the subplate neurons.

Understanding early human brain development is of great clinical importance, as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral organization and maturation. Technological advances in neonatal brain imaging are progressively giving more insights for the understanding of disorders of neonatal brain. In these population of preterm babies the need for al-ways more sophisticated neuro radiological studies has to be accompanied by improved skills in identifying even those very subtle clinical signs of impairment

deserving further investigations. In this way we may hope to better understand why some studies highlight that the risk of developmental delay or disability was 36% higher among late preterm infants compared with term infants (26).

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Correspondance:Luca Romenghi, MDTerapia Intensiva NeonataleIstituto Giannina Gaslini IRCCSGenova, ItalyE-mail: patologianeonatale@ospedale-gaslini.ge.it