5 th International Workshop on Neonatology The Future of European Neonatology Cagliari, October 30-31, 2009 Non Steroids Anti-inflammatory Drugs in the

5th International Workshop on Neonatology The Future of European Neonatology

Cagliari, October 30-31, 2009

Non Steroids Anti-inflammatory Drugs in the treatment of PDA in European Newborns

Hercília GuimarãesOn the behalf of the Collaborative Study

NSAIDs to treat PDA in European Newborns

Introduction I

PDA is a common cause of morbidity and mortality among VLBW infants.

The clinical decision of treating PDA should be carried out on an individual basis, according to the clinical condition of the newborn, its hemodynamic importance and potential risks.

Echocardiographic evaluation is necessary to establish the diagnosis and to follow the treatment.


Introduction II

Indomethacin and ibuprofen, NSAIDs, used in the treatment of PDA in preterm newborn infants have been shown to produce closure in approximately 85% of patients.

The choice for Indomethacin or Ibuprofen should be established after evaluation of the clinical condition, costs and local or regional availability


Aim

To know the European reality on NSAIDs in the treatment of PDA in preterm newborns.


Material and Methods

A questionnaire to be filled was sent to:

• Presidents of the 24 European Societies of Neonatology/ Perinatology (UENPS)

and

• 3 representatives NICUs in Europe (UK, Belgium, Germany)

NSAIDs in the treatment of PDA in European newbornsQuestionnaire

Country and NICU What drugs do you use in your country to treat PDA?

Ibuprofen (iv) No ____Yes ____ Doses _________Ibuprofen (oral) No ____Yes ____ Doses _____________Indomethacin (iv) No ____Yes ____ Doses____________Indomethacin (iv) Perfusion 30 min_____ 60 min__________ Others_________________

How many courses of treatment do you use? 1___ 2 ____3______ Do you use prolonged treatment? No __ Yes_____ Doses ____ How many days? ____ In which babies?______ Why do you prefer ibuprofen ? ______________________________ Why do you prefer indomethacin ? _____________________ When do you use NSAIDs?

Prophylactic treatment No________ Yes___________PDA no hemodynamically significant No_______Yes ___________PDA hemodynamically significant No________ Yes __________

Do you use fluid restriction with NSAIDs ? No___ Yes __ If yes, how much (ml/kg) __________ Do you stop oral feeding during NSAIDs ? No_____ Yes ______ Do you use diuretics: No_____ Yes ____Which?_____ Do you diagnose PDA on a clinical basis only ? No________ Yes ________ Do you diagnose PDA by echocardiography ? No________ Yes ________ Which echocardiography criteria do you use to PDA hemodinamically significant:

Ductal diameter of >1.4mm No___ Yes ________Left atrial:aortic root >1.3:1 No________ Yes _______Retrograde diastolic flow in descending aorta exceeding 30% of anterograde flow: No__Yes __

Other criteria_________________ Do you monitor PDA by echo ? No___ Yes____ Examinations during a course__________________

NSAIDs in the treatment of PDA in European newbornsQuestionnaire

What contra-indications do you consider to NSAIDs treatment? Indomethacin Ibuprofen Platelets < 25.000 Creat. > 2.5 mg/dl (or >___) Oliguria NEC HIV Bleeding Others When do you propose surgical closure of PDA?

1. After failure of : 1___ 2__ 3 ___ 4______ courses of treatment2 .After 3 weeks of life No ___ Yes _____3 .Before 3 weeks of life No ____ Yes___4. In babies < 1000g No ____ Yes ____5. Contra-indications to medical treatment No_____ Yes___

Please Indicate Ibuprofen solution__________________________________

Are your choices influenced by Administration economical reasons?

Number of babies with PDA / year in your NICU?__________________ Number of Admission / year in your Unit?__________________________ Number of Admission / year of VLBW in your Unit?_________________

Comments


Results

45 NICUs from 19 countries filled the questionnaire:

1 (2 %) - North

26 (58 %) - South

12 (27 %) - East

6 (13 %) - West

Number of admissions, VLBW infants and PDA / year

n=45 Mean SD Median (min – max)

Admissions 441+234 372 (125–1300)

VLBW infants 102+90 81 (4–550)

PDA 38+31 30 (2–150)

% PDA/ admissions 9+ 6 9 (0.4–25)

% PDA/ VLBW infants 41+20 39 (3–100)

PDA=patent ductus arteriosus; VLBW infants

NSAIDs to treat PDA in the European newborns

n=45n (%) Number of doses †

Ibuprofen intravenous oral rectal

16 (36)13 (29)

1 (2)

33*3*

Indomethacin intravenous intramuscular

32 (71)1 (2)

3**

1 NICU does not use NSAIDs; † 2 NICUs use prolonged treatment in all cases; * 2 NICUs use 2 doses; ** 3 NICUs use 4 and 5 doses

Indomethacin and Ibuprofen

The perfusion of Indomethacin is done during :30 minutes in 20 (63%) NICUs

60 minutes in 8 (25%)20 minutes in one.

The number of treatment courses used is :2 in 20 (45 %) NICUs3 in 12 (27 %) NICUs

more than 3 courses in 21 NICU uses 2 courses of Ibuprofen + 1of Indomethacin


Prolonged treatment (4-6 days) was mentioned by 20 (45%) NICUs.

The selected newborns to prolonged treatment are: failure of 3 treatment courses in 7 (35 %)

< 1500g in 6 (30 %) < 1000g in 3 (15 %)

all babies in 2 critical conditions in 1 Ibuprofen failure in 1


Prophylactic treatment is used in 2 NICUs

11 (25%) treat no hemodynamically significant PDA

43 (98%) treat hemodynamically significant PDA.

1 NICU uses surgical closure as first line treatment.


Fluid restriction during NSAIDs treatment in 36 (80%) NICUs

the percentage of restriction is 20% in 9 NICUs and 30% in 5.

9 (20%) NICUs stop oral feeding during NSAIDs treatment.

Diuretics are used in 22 (49%) NICUs: furosemide in 19 (86%)

furosemide and/or spironolactone in 3 (+ NSAIDs)


The diagnosis of PDA is confirmed by echocardiography in all NICUs.

The echocardiographic criteria of hemodynamically significant PDA are:

ductal diameter >1.4mm in 28 (64%) NICUs;

left atrial:aortic root >1.3:1 in 31 (70%);

retrograde diastolic flow in desc. aorta>30% of anterograde flow in 24 (55%)

15 (34 %) use other criteria.

37(82%) NICUs monitor PDA by echocardiography.


Surgical closure of PDA is proposed :

after failure of 1, in 2 (5 %), 2, in 20 (45 %), and >3, and 12 (27 %) NICUs

after 3 weeks of life in 24 (53 %)

before 3 weeks of life in 12 (27 %)

in babies < 1000g, in 17 (39%)

contra-indications to NSAIDs in 27 (61 %)


PedeaR is the iv Ibuprofen solution used

Ibuprofen oral solution has a concentration of 20mg/ml.

Contra-indications for NSAIDs treatment

Indomethacin(n=33), n (%)

Ibuprofen(n=30), n (%

Platelets < 25.000 231* (94) 24* (80)

Creatinine ≥ 2.5 mg/dl 22** (67) 18*** (60)

Oligury 33 (100) 16 (53)

NEC 33 (100) 24 (80)

IVH 19 (58) 13 (43)

Bleeding (active) 30 (91) 22 (73)

Others ETcriteria heart failure infection

1 (3)1 (3)1(3)

2 (7)1 (3)1 (3)

*1 NICU uses < 30.000; **3 NICUs use > 1.5 mg/dl and 1 NICU uses > 1.8 mg/dl; *** 2 NICUs use > 1.5 mg/dl

Indomethacin and Ibuprofen preference

Indomethacin(n=33), n (%)

Ibuprofen(n=30), n (%)

Safety 2 (6) 15 (50)

Effectiveness 4 (12) 3 (10)

Cost 10 (30) 6* (20)

Experience 12** (36) 4*** (13)

* oral Ibuprofen; ** only Indomethacin was available in 5 NICUs ;*** only oral Ibuprofen was available


The choices are influenced by economical

reasons in 10 (22%) NICUs.


Conclusion

Our data show a wide variation among NICUs and countries regarding the use of NSAIDs to treat PDA and no general guidelines are followed.

Guidelines or recommendations are necessary to treat PDA in Europe, giving all newborns identical health care opportunities.

Collaborators Belgium: B. van Overmeire, University of Antwerp. Bósnia and Herzegovinia: S. Heljic, Clinical University Sarajevo; S. Bajic,

Cardiology, Clinical Centre Banja Luka. Bulgary: N. Jekova, Neonatology, Specialized Hospital of Obstetrics and

Gynecology "Maichin dom", Sofia. Croatia: Emilja Ejuretic,NICU Clinical Hospital Zagreb. Estonia: Tuuli Metsvaht, Tartu Paediatric and Neonatal Intensive. France: P-H. Jarreau, Port-Royal, Paris; J.C. Picaud, Hôpital de la Croix

Rouge, Lyon. Germany: A.Franz, University of Tuebingen. Greece: F. Anatolitou, Agia Sophia Children Hospital, Athens; K. Sarafidis,

Hippokration General Hospital, Thessaloniki; Andreou A Hippokration, General Hospital Thessaloniki; Mitsiakos G. Papageorgiou, General Hospital Thessaloniki; Mousafiris K, Interbalcan Medical Center Thessaloniki; Galanopoulou A., Agios Andreas Hospital, Patras; Sigalas I, University General Hospital Alexandroupolis; Andronikou S, University Hospital of Ioannina; Papadimitriou M, Aglaia Kyraikou Children Hospital, Athens; Siokou E, Lito Maternity Hospital Athens, Kostantinou D, Iaso Maternity Hospital, Athens Gounaris A, Nikaia General Hospital, Piraeus.

Hungary: T. Kovacs, Medical and Health Science Center, Debrecen.

Collaborators Italy: V. Fanos, Neonatal Intensive Care Unit, University of Cagliari; M.

Pusceddu, Cesena. Macedonia: K.Piperkova. Netherlands: J.B. van Goudoever, Erasmus MC/Sophia Children's Hospital,

Rotterdam. Portugal: A.Freitas, Hospital Senhora da Oliveira, Guimarães; E. Proença,

Maternidade Júlio Dinis, Porto; A. Pereira, Hospital de S. Marcos, Braga; A. Salazar, Hospital S. Francisco Xavier, Lisboa; D. Virella, Hospital d. Estefânia, Lisboa; H. Guimarães, G. Rocha, São João Hospital, Porto University; T. Tomé, Maternidade Alfredo da Costa, Lisboa; S. Pedro Frutuoso, Hospital de Santo António, Porto; G. Mimoso, Maternidade Bissaya Barreto, Coimbra.

Romania: S. Silvia, Bucharest; Tg- Mures; Iasi. Spain: M. Sanchez-Luna, Gregorio Maragnon Hospital, Madrid; J. Pérez, La

Paz Hospital, Madrid. Slovakia: F. Bauer, Nové Zámky; M. Zibolen, University Hospital Martin; Slovenia: J. Babnik, University Medical Centre, Ljubjana. Turkey: M. Yurdakok, Hacettepe University, Istanbul. United Kingdom: N. Modi, Imperial College, London.

Thank you very muchfor your atention

Porto and River Douro

Documents

5 th International Workshop on Neonatology The Future of European Neonatology Cagliari, October 30-31, 2009 Non Steroids Anti-inflammatory Drugs in the