- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02940327
Markers of Inflammation and Lung Recovery in ECMO Patients for PPHN (Mi-ECMO)
March 4, 2020 updated by: University of Leicester
A Feasibility Study to Consider the Relationship Between Markers of Red Cell Damage, Inflammation and the Recovery Process of Newborns Requiring Extracorporeal Membrane Oxygenation (ECMO) for Persistent Pulmonary Hypertension of the Newborn (PPHN): Mi-ECMO
Respiratory failure in newborns is common and has high rates of death.
Where conventional intensive care strategies have failed, newborn children are referred to treatment with Extra- Corporeal Membrane Oxygenation (ECMO).
This involves connecting children via large bore cannulas placed in their heart and major blood vessels to an artificial lung that adds oxygen to their blood and removes waste gases (carbon dioxide).
Although this treatment saves lives, it still has some limitations.
In particular, severe complications like bleeding, or damage to the kidneys can occur.
These complications can lead to death in some cases and long-term disability in others.
Based on ongoing research in adults and children undergoing cardiac surgery the investigators have identified a new process that may underlie some of the complications observed in ECMO.
The investigators have noted that when transfused blood is infused in an ECMO circuit, this results in the accelerated release of substances from the donor cells that cause organ damage; at least in adults.
There are treatments that can reverse this process.
Before the investigators explore whether these treatments should be used in newborn children on ECMO, the investigators must first demonstrate that they can measure the complex inflammatory processes that occur in these critically ill children.
The investigators therefore propose to conduct a feasibility study to identify the practical issues and challenges that would need to be overcome in order to perform a successful trial in this high-risk population.
Study Overview
Status
Completed
Detailed Description
The primary hypothesis is that damage to red blood cells by the exposure to the ECMO circuit will result in inflammatory responses that mitigate against successful weaning from Extra-Corporeal Membrane Oxygenation (ECMO) for Persistent Pulmonary Hypertension of the Newborn (PPHN).
The secondary hypothesis are:
- Damage to red cells will result in platelet, leukocyte and endothelial activation.
- Markers of platelet, endothelial and leukocyte activation are indicators of lung inflammation and injury severity and hence lung recovery.
- Markers of platelet, endothelial and leukocyte activation are indicators of kidney injury severity and hence acute kidney injury.
- The level of oxidative stress will correlate with type shifts in pulmonary macrophages, tissue iron deposition and organ injury.
- Ability to raise anti-oxidative response, measured by Heme Oxigenase-1 (HMOX 1) expression, will correlate with shorter intubation times and less severe kidney and lung injury.
- Granulocyte and platelets activation are secondary to rising redox potential and the levels of activation will correlate with longer intubation times and more severe organ injury.
- Markers of anti-oxidative response, platelet, endothelial and leukocyte activation, as well as oxidative stress levels have diagnostic and prognostic utility for the prediction of key clinical events including delayed time to recovery, acute kidney injury in paediatric patients undergoing Extra-Corporeal Membrane Oxygenation (ECMO) for Persistent Pulmonary Hypertension of the Newborn (PPHN).
This is a pilot feasibility study that will establish the following:
- Recruitment rates and patient flows for 24 patients specified as the target population for the feasibility study
- Withdrawal rate, and completeness of follow-up and data collection in a paediatric population at high risk for death and major morbidity
- The proportions (categorical data) and variance (continuous data) for the primary and secondary outcomes of interest. These will be used to model the sample sizes and outcomes that may be used in a definitive study
- Perceptions of family members whose children participate in the study as to the appropriateness of the screening and consent process
Study Type
Observational
Enrollment (Actual)
24
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Leicester, United Kingdom, LE3 9QP
- University Hospitals Of Leicester Nhs Trust
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
No older than 4 weeks (Child)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Sampling Method
Probability Sample
Study Population
The study will be conducted at a regional ECMO centre in the UK, the University Hospitals of Leicester NHS Trust.
This unit performs over 60 neonatal and paediatric ECMO per year, of which at least 40 are expected to be performed for the treatment of PPHN in infants.
Description
Inclusion Criteria:
- Patients with a diagnosis of PPHN
- Patients that require ECMO support as determined by the ECMO team
- Patients aged less than 30 days
- Emergency consent obtained within 12 hours from cannulation, and ultimately full consent
Exclusion Criteria:
- PPHN is caused by a congenital heart pathology
- ECMO is required for a congenital heart disease
- Lack of consent
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Observational Models: Case-Control
- Time Perspectives: Prospective
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CD16/41
Time Frame: 12 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
12 hours after ECMO commencement
|
CD16/41
Time Frame: 24 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
24 hours after ECMO commencement
|
CD16/41
Time Frame: 48 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
48 hours after ECMO commencement
|
CD16/41
Time Frame: 72 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
72 hours after ECMO commencement
|
CD16/41
Time Frame: 24 hours after decannulation
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
24 hours after decannulation
|
CD14/41
Time Frame: 12 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
12 hours after ECMO commencement
|
CD14/41
Time Frame: 24 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
24 hours after ECMO commencement
|
CD14/41
Time Frame: 48 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
48 hours after ECMO commencement
|
CD14/41
Time Frame: 72 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
72 hours after ECMO commencement
|
CD14/41
Time Frame: 24 hours after ECMO decannulation
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
24 hours after ECMO decannulation
|
CD64/163
Time Frame: 12 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
12 hours after ECMO commencement
|
CD64/163
Time Frame: 24 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
24 hours after ECMO commencement
|
CD64/163
Time Frame: 48 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
48 hours after ECMO commencement
|
CD64/163
Time Frame: 72 hours after ECMO commencement
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
72 hours after ECMO commencement
|
CD64/163
Time Frame: 24 hours after decannulation
|
Change of markers of platelet and leukocyte activation in arterial blood and analysed by flow cytometry.
|
24 hours after decannulation
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change of Serum Haemoglobin Levels
Time Frame: baseline
|
Clinical and biochemical markers of organ failure
|
baseline
|
Duration on ECMO
Time Frame: > 7 days or did not survive to discharge
|
Clinical and biochemical markers of organ failure
|
> 7 days or did not survive to discharge
|
Number of Participants With Acute Kidney Injury
Time Frame: >7 days or did not survive to discharge
|
Clinical and biochemical markers of organ failure
|
>7 days or did not survive to discharge
|
Heart Injury as Determined by Serum Troponin Levels
Time Frame: 12 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
12 hours after ECMO commencement
|
Allogenic Red Cell Transfusion Volume
Time Frame: 24 hours after ECMO is discontinued
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Clinical and biochemical markers of organ failure
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24 hours after ECMO is discontinued
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Number of Participants Requiring Non Red Cell Transfusion
Time Frame: 24 hours after ECMO is discontinued
|
Clinical and biochemical markers of organ failure
|
24 hours after ECMO is discontinued
|
Heart Injury as Determined by Serum Troponin Levels
Time Frame: 24 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
24 hours after ECMO commencement
|
Heart Injury as Determined by Serum Troponin Levels
Time Frame: 48 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
48 hours after ECMO commencement
|
Heart Injury as Determined by Serum Troponin Levels
Time Frame: 72 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
72 hours after ECMO commencement
|
Heart Injury as Determined by Serum Troponin Levels
Time Frame: 24 hours after decannulation
|
Clinical and biochemical markers of organ failure
|
24 hours after decannulation
|
Change of Serum Haemoglobin Levels
Time Frame: 12 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
12 hours after ECMO commencement
|
Change of Serum Haemoglobin Levels
Time Frame: 24 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
24 hours after ECMO commencement
|
Change of Serum Haemoglobin Levels
Time Frame: 48 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
48 hours after ECMO commencement
|
Change of Serum Haemoglobin Levels
Time Frame: 72 hours after ECMO commencement
|
Clinical and biochemical markers of organ failure
|
72 hours after ECMO commencement
|
Change of Serum Haemoglobin Levels
Time Frame: 24 hours after decannulation
|
Clinical and biochemical markers of organ failure
|
24 hours after decannulation
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Warren OJ, Smith AJ, Alexiou C, Rogers PL, Jawad N, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass: part 1--mechanisms of pathogenesis. J Cardiothorac Vasc Anesth. 2009 Apr;23(2):223-31. doi: 10.1053/j.jvca.2008.08.007. Epub 2008 Oct 19. No abstract available.
- Mamikonian LS, Mamo LB, Smith PB, Koo J, Lodge AJ, Turi JL. Cardiopulmonary bypass is associated with hemolysis and acute kidney injury in neonates, infants, and children*. Pediatr Crit Care Med. 2014 Mar;15(3):e111-9. doi: 10.1097/PCC.0000000000000047.
- Schaible T, Hermle D, Loersch F, Demirakca S, Reinshagen K, Varnholt V. A 20-year experience on neonatal extracorporeal membrane oxygenation in a referral center. Intensive Care Med. 2010 Jul;36(7):1229-34. doi: 10.1007/s00134-010-1886-5. Epub 2010 Apr 28.
- Mugford M, Elbourne D, Field D. Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD001340. doi: 10.1002/14651858.CD001340.pub2.
- Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin North Am. 2009 Jun;56(3):579-600, Table of Contents. doi: 10.1016/j.pcl.2009.04.004.
- Bahrami KR, Van Meurs KP. ECMO for neonatal respiratory failure. Semin Perinatol. 2005 Feb;29(1):15-23. doi: 10.1053/j.semperi.2005.02.004.
- UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet. 1996 Jul 13;348(9020):75-82.
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- Lazar DA, Cass DL, Olutoye OO, Welty SE, Fernandes CJ, Rycus PT, Lee TC. The use of ECMO for persistent pulmonary hypertension of the newborn: a decade of experience. J Surg Res. 2012 Oct;177(2):263-7. doi: 10.1016/j.jss.2012.07.058. Epub 2012 Aug 10.
- McNally H, Bennett CC, Elbourne D, Field DJ; UK Collaborative ECMO Trial Group. United Kingdom collaborative randomized trial of neonatal extracorporeal membrane oxygenation: follow-up to age 7 years. Pediatrics. 2006 May;117(5):e845-54. doi: 10.1542/peds.2005-1167. Epub 2006 Apr 24.
- Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol. 2005 Feb;29(1):8-14. doi: 10.1053/j.semperi.2005.02.003.
- Bendapudi P, Rao GG, Greenough A. Diagnosis and management of persistent pulmonary hypertension of the newborn. Paediatr Respir Rev. 2015 Jun;16(3):157-61. doi: 10.1016/j.prrv.2015.02.001. Epub 2015 Feb 10.
- Puthiyachirakkal M, Mhanna MJ. Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr. 2013 Sep 2;1:23. doi: 10.3389/fped.2013.00023.
- McILwain RB, Timpa JG, Kurundkar AR, Holt DW, Kelly DR, Hartman YE, Neel ML, Karnatak RK, Schelonka RL, Anantharamaiah GM, Killingsworth CR, Maheshwari A. Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine. Lab Invest. 2010 Jan;90(1):128-39. doi: 10.1038/labinvest.2009.119. Epub 2009 Nov 9.
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- Butler J, Pathi VL, Paton RD, Logan RW, MacArthur KJ, Jamieson MP, Pollock JC. Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Ann Thorac Surg. 1996 Aug;62(2):538-42.
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- Day JR, Taylor KM. The systemic inflammatory response syndrome and cardiopulmonary bypass. Int J Surg. 2005;3(2):129-40. doi: 10.1016/j.ijsu.2005.04.002. Epub 2005 Aug 1.
- Warren OJ, Watret AL, de Wit KL, Alexiou C, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass: part 2--anti-inflammatory therapeutic strategies. J Cardiothorac Vasc Anesth. 2009 Jun;23(3):384-93. doi: 10.1053/j.jvca.2008.09.007. Epub 2008 Dec 3. No abstract available.
- Williams DC, Turi JL, Hornik CP, Bonadonna DK, Williford WL, Walczak RJ, Watt KM, Cheifetz IM. Circuit oxygenator contributes to extracorporeal membrane oxygenation-induced hemolysis. ASAIO J. 2015 Mar-Apr;61(2):190-5. doi: 10.1097/MAT.0000000000000173.
- Omar HR, Mirsaeidi M, Socias S, Sprenker C, Caldeira C, Camporesi EM, Mangar D. Plasma Free Hemoglobin Is an Independent Predictor of Mortality among Patients on Extracorporeal Membrane Oxygenation Support. PLoS One. 2015 Apr 22;10(4):e0124034. doi: 10.1371/journal.pone.0124034. eCollection 2015.
- Lou S, MacLaren G, Best D, Delzoppo C, Butt W. Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes. Crit Care Med. 2014 May;42(5):1213-20. doi: 10.1097/CCM.0000000000000128.
- Lubnow M, Philipp A, Foltan M, Bull Enger T, Lunz D, Bein T, Haneya A, Schmid C, Riegger G, Muller T, Lehle K. Technical complications during veno-venous extracorporeal membrane oxygenation and their relevance predicting a system-exchange--retrospective analysis of 265 cases. PLoS One. 2014 Dec 2;9(12):e112316. doi: 10.1371/journal.pone.0112316. eCollection 2014.
- Maslach-Hubbard A, Bratton SL. Extracorporeal membrane oxygenation for pediatric respiratory failure: History, development and current status. World J Crit Care Med. 2013 Nov 4;2(4):29-39. doi: 10.5492/wjccm.v2.i4.29. eCollection 2013 Nov 4.
- Toomasian JM, Bartlett RH. Hemolysis and ECMO pumps in the 21st Century. Perfusion. 2011 Jan;26(1):5-6. doi: 10.1177/0267659110396015. No abstract available.
- Smith A, McCulloh RJ. Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders. Front Physiol. 2015 Jun 30;6:187. doi: 10.3389/fphys.2015.00187. eCollection 2015.
- Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW. Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development. Front Physiol. 2014 Oct 28;5:415. doi: 10.3389/fphys.2014.00415. eCollection 2014.
- Hanssen SJ, van de Poll MC, Houben AJ, Windsant IC, Snoeijs MG, Bekers O, Buurman WA, Jacobs MJ. Hemolysis compromises nitric oxide-dependent vasodilatory responses in patients undergoing major cardiovascular surgery. Thorac Cardiovasc Surg. 2012 Jun;60(4):255-61. doi: 10.1055/s-0031-1299571. Epub 2012 Mar 12.
- Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005 Apr 6;293(13):1653-62. doi: 10.1001/jama.293.13.1653.
- Vermeulen Windsant IC, de Wit NC, Sertorio JT, van Bijnen AA, Ganushchak YM, Heijmans JH, Tanus-Santos JE, Jacobs MJ, Maessen JG, Buurman WA. Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage. Front Physiol. 2014 Sep 8;5:340. doi: 10.3389/fphys.2014.00340. eCollection 2014.
- Vermeulen Windsant IC, Hanssen SJ, Buurman WA, Jacobs MJ. Cardiovascular surgery and organ damage: time to reconsider the role of hemolysis. J Thorac Cardiovasc Surg. 2011 Jul;142(1):1-11. doi: 10.1016/j.jtcvs.2011.02.012. Epub 2011 May 13. No abstract available.
- Haase M, Bellomo R, Haase-Fielitz A. Novel biomarkers, oxidative stress, and the role of labile iron toxicity in cardiopulmonary bypass-associated acute kidney injury. J Am Coll Cardiol. 2010 May 11;55(19):2024-33. doi: 10.1016/j.jacc.2009.12.046.
- Irwin DC, Baek JH, Hassell K, Nuss R, Eigenberger P, Lisk C, Loomis Z, Maltzahn J, Stenmark KR, Nozik-Grayck E, Buehler PW. Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration. Free Radic Biol Med. 2015 May;82:50-62. doi: 10.1016/j.freeradbiomed.2015.01.012. Epub 2015 Feb 2.
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Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
February 19, 2016
Primary Completion (Actual)
July 10, 2017
Study Completion (Actual)
July 10, 2017
Study Registration Dates
First Submitted
October 13, 2016
First Submitted That Met QC Criteria
October 18, 2016
First Posted (Estimate)
October 20, 2016
Study Record Updates
Last Update Posted (Actual)
March 19, 2020
Last Update Submitted That Met QC Criteria
March 4, 2020
Last Verified
May 1, 2018
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 0553
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Yes
IPD Plan Description
statistical analysis
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Persistent Pulmonary Hypertension of the Newborn
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Pfizer's Upjohn has merged with Mylan to form Viatris...CompletedPulmonary Hypertension, Familial Persistent, of the NewbornUnited States, Belgium, United Kingdom, Spain, Denmark, Germany, Sweden, Canada, France, Italy, Netherlands, Norway
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Alexandria UniversityRecruitingPersistent Pulmonary Hypertension of the Newborn | Respiratory Disease | EchocardiographyEgypt
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Sohag UniversityCompletedPersistent Pulmonary Hypertension of the Newborn | PPHN | Persistent Fetal CirculationEgypt
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Medical College of WisconsinRecruitingPersistent Pulmonary Hypertension of the NewbornUnited States
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Shandong UniversityWest China Second University HospitalNot yet recruitingPersistent Pulmonary Hypertension of the NewbornChina
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United TherapeuticsTerminatedPersistent Pulmonary Hypertension of the NewbornUnited States
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Pfizer's Upjohn has merged with Mylan to form Viatris...WithdrawnPersistent Pulmonary Hypertension of the Newborn
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ActelionTerminatedPersistent Pulmonary Hypertension of the NewbornUnited States, Australia, Belgium, Czech Republic, France, Germany, Korea, Republic of, Poland, Russian Federation, Singapore, Switzerland, United Kingdom
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Emory UniversityCompletedPulmonary HypertensionUnited States
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University Hospital, ToulouseCompletedPersistent Pulmonary Hypertension of the NewbornFrance