Physiological Umbilical Cord Clamping in Patients With Congenital Diaphragmatic Hernia. Clinical Trial

Overview

Congenital diaphragmatic hernia (CDH) is a malformation that affects 1 in every 3000 newborns. The diaphragm does not complete its closure during embryogenesis, which allows the abdominal organs to herniate into the thoracic cavity altering lung development. The lungs of patients with CDH are small, with a decreased surface area for gas exchange and developmental impair of the pulmonary vasculature, resulting in respiratory failure and pulmonary hypertension shortly after birth. When clamping the umbilical cord, a large part of the preload is abruptly excluded, generating an increase in vascular resistance, which in turn increase the afterload, resulting in a decrease in cardiac output. The output is restored by decreasing vascular resistance in pulmonary circuit after lung aeration upon receiving the preload of the right atrium, increasing pulmonary flow and thus sustaining the preload of the left ventricle. If pulmonary aeration occurs before clamping the umbilical cord, the pulmonary blood flow increases before placenta flow is lost, thus avoiding a decrease in cardiac output. This modality has been called physiological base cord clamping (PFC). The hypothesis is that PFC once ventilation has been established could prevent hypoxia and improve cardiac output in newborns with CDH and secondarily improve their hemodynamic parameters, stabilizing gas exchange and pulmonary hypertension during the first 24 hours of birth.

Detailed description

* Type of study: Randomized clinical trial * Primary objective: To establish the effectiveness of PFC in reducing hypoxia and improving cardiac output compared to immediate postintubation clamping in newborns with CDH. To establish the safety and feasibility of PFC after pulmonary recruitment achieved post intubation. * Secondary objectives: describe the evolution of patients with CDH 24 hours after birth under pre-established conditions. Relate prenatal indices to the subsequent evolution of these patients. Describe maternal evolution and postpartum complications. * Population: Patients who attend the Fetal Diagnosis and Treatment program of Garrahan Children's Hospital and undergo prenatal diagnosis of CDH are possible candidates. The study will be carried out in the Neonatal Intensive Care Unit of said hospital. * Scope of the study: Garrahan Children's Hospital is a level 3 B pediatric hospital and national referral center located in Autonomous City of Buenos Aires, Argentina. Center that receives neonates with CDH referred from all over the country as well as from other countries in the region and carries out the relevant training for equal reception. * Block randomization: will be carried out on the same day, 2 hours before entering the delivery room * Intervention: Immediately after birth, the newborn will be placed on a mobile table, made to received these patients in the delivery room, at the level of the mother's womb, leaving the umbilical cord intact, intubated and gently ventilated (positive inspiration pressure (PIM) 15/25 - positive end expiratory pressure (PEEP)4 - fraction of inspired oxygen inspired oxygen fraction (FiO2) 50%), until saturation \>85% and heart rate (HR) \>100 or 10 timed minutes pass, whichever occurs first, the umbilical cord will be clamped and continued with the usual reception steps in accordance with the unit´s CDH reception protocol. * Sample size: To calculate the sample size, a prevalence of hemodynamic alterations of 60% was considered in the first 24 hours of life of patients with CDH, following unit statistics and the aforementioned bibliography. The estimated sample size with a relative reduction of 50%: reduction from 60% to 30% of hemodynamic alterations - Power of 80% - Two-tailed test - alpha 5%. 40 patients required in each branch.

Interventions

• Procedure Physiological cord clamping
  Immediately after birth, the newborn with prenatal diagnosis of CDH will be placed on a mobile table, made to receive these patients in the delivery room, at the level of the mother's womb, leaving the umbilical cord intact and intubated. The patient will be gently ventilated (PIM 15/25 - PEEP 4 - Fio2 50%), until saturation \>85% and HR\>100 or 10 timed minutes have elapsed, whichever occurs first, the umbilical cord will be clamped.

Primary outcome measures

• Hemodynamic deterioration in the first 24 hours of life [Time frame: 24 hours of life]
• complete delivery according group [Time frame: delivery]

Secondary outcome measures (12)

• Gestational age at diagnosis [Time frame: 1st day of life]
• Lung heart rate index observed/expected LHR O/E [Time frame: from 26 to 32 weeks of gestational age]
• liver in thorax [Time frame: from 26 to 32 weeks of gestational age]
• stomach herniation [Time frame: from 26 to 32 weeks of gestational age]
• lung volumen [Time frame: from 26 to 32 weeks of gestational age]
• Mcgoon [Time frame: from 26 to 32 weeks of gestational age]
• maternal hematocrit [Time frame: 1 day before delivery]
• Intubation time [Time frame: From delivery to intubation]
• Cord clamping time [Time frame: from delivery to cord clamping]
• Advance resuscitation need on delivery room [Time frame: from delivery to 30 minutes of life]
• Time to reach heart rate (HR) >100 [Time frame: from delivery to 30 minutes of life]
• Time to reach saturation (SAT) >85% [Time frame: from delivery to 30 minutes of life]

Eligibility criteria

Inclusion criteria

• Prenatal diagnosis of congenital diaphragmatic hernia
• gestational age >34 weeks
• Informed consent signed by the patient's parents

Exclusion criteria

• Multiple gestation
• Major malformation or fetal genetic anomaly diagnosed in the prenatal stage
• Emergency cesarean section or maternal condition that prevents the approach
• Lack of informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Single blind

Primary purpose

Prevention

Study locations

Argentina · 1 center

• Hospital de Pediatría S.A.M.I.C. "Prof. Dr. Juan P. Garrahan" — Buenos Aires

Publications

• Langham MR Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia. Epidemiology and outcome. Clin Perinatol. 1996 Dec;23(4):671-88. PMID 8982563
• Keller RL. Antenatal and postnatal lung and vascular anatomic and functional studies in congenital diaphragmatic hernia: implications for clinical management. Am J Med Genet C Semin Med Genet. 2007 May 15;145C(2):184-200. doi: 10.1002/ajmg.c.30130. PMID 17436304
• Snoek KG, Reiss IK, Greenough A, Capolupo I, Urlesberger B, Wessel L, Storme L, Deprest J, Schaible T, van Heijst A, Tibboel D; CDH EURO Consortium. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology. 2016;110(1):66-74. doi: 10.1159/000444210. Epub 2016 Apr 15. PMID 27077664
• Bhatt S, Alison BJ, Wallace EM, Crossley KJ, Gill AW, Kluckow M, te Pas AB, Morley CJ, Polglase GR, Hooper SB. Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs. J Physiol. 2013 Apr 15;591(8):2113-26. doi: 10.1113/jphysiol.2012.250084. Epub 2013 Feb 11. PMID 23401615
• Polglase GR, Dawson JA, Kluckow M, Gill AW, Davis PG, Te Pas AB, Crossley KJ, McDougall A, Wallace EM, Hooper SB. Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) improves systemic and cerebral oxygenation in preterm lambs. PLoS One. 2015 Feb 17;10(2):e0117504. doi: 10.1371/journal.pone.0117504. eCollection 2015. PMID 25689406
• Hooper SB, Te Pas AB, Lang J, van Vonderen JJ, Roehr CC, Kluckow M, Gill AW, Wallace EM, Polglase GR. Cardiovascular transition at birth: a physiological sequence. Pediatr Res. 2015 May;77(5):608-14. doi: 10.1038/pr.2015.21. Epub 2015 Feb 4. PMID 25671807
• Horn-Oudshoorn EJJ, Knol R, Te Pas AB, Hooper SB, Cochius-den Otter SCM, Wijnen RMH, Schaible T, Reiss IKM, DeKoninck PLJ. Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts. Arch Dis Child Fetal Neonatal Ed. 2020 Jul;105(4):449-454. doi: 10.1136/archdischild-2019-318606. Epub 2020 Mar 13. PMID 32170029
• Hooper SB, Polglase GR, te Pas AB. A physiological approach to the timing of umbilical cord clamping at birth. Arch Dis Child Fetal Neonatal Ed. 2015 Jul;100(4):F355-60. doi: 10.1136/archdischild-2013-305703. Epub 2014 Dec 24. PMID 25540147

Identifiers

NCT: NCT06408376 · 1362 · 6721

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗