Clinical trial NCT06408376: Physiological Umbilical Cord Clamping in Patients With Congenital Diaphragmatic Hernia. Clinical Trial
Official title: Physiological Umbilical Cord Clamping in Patients With Congenital Diaphragmatic Hernia. Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Umbilical Cord Clamping
Congenital Diaphragmatic Hernia
Delayed Umbilical Cord Separation
Lead sponsor: Hospital JP Garrahan
Sponsor class: OTHER_GOV
First posted: 2024-05-10
Enrollment: 80
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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.

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

Primary outcomes:
measure: Hemodynamic deterioration in the first 24 hours of life
timeFrame: 24 hours of life
measure: complete delivery according group
timeFrame: delivery
Secondary outcomes:
measure: Gestational age at diagnosis
timeFrame: 1st day of life
measure: Lung heart rate index observed/expected LHR O/E
timeFrame: from 26 to 32 weeks of gestational age
measure: liver in thorax
timeFrame: from 26 to 32 weeks of gestational age
measure: stomach herniation
timeFrame: from 26 to 32 weeks of gestational age
measure: lung volumen
timeFrame: from 26 to 32 weeks of gestational age
measure: Mcgoon
timeFrame: from 26 to 32 weeks of gestational age
measure: maternal hematocrit
timeFrame: 1 day before delivery
measure: Intubation time
timeFrame: From delivery to intubation
measure: Cord clamping time
timeFrame: from delivery to cord clamping
measure: Advance resuscitation need on delivery room
timeFrame: from delivery to 30 minutes of life
measure: Time to reach heart rate (HR) >100
timeFrame: from delivery to 30 minutes of life
measure: Time to reach saturation (SAT) >85%
timeFrame: from delivery to 30 minutes of life
measure: Cord PH value
timeFrame: inmediatly after cord clampping
measure: Cord lactic acid value
timeFrame: inmediatly after cord clampping
measure: saturation at 10 minutes
timeFrame: 10 minutes of life
measure: Arterial pressure at 10 minutes
timeFrame: 10 minutes of life
measure: placenta abruption
timeFrame: 30 minutes of life
measure: Mother arterial tension after delivery
timeFrame: 10 minutes after delivery
measure: Uterotonic use
timeFrame: 30 minutes after delivery
measure: Evolution of patient Blood preassure (BP)
timeFrame: 2 - 4 hours and 24 hours of life
measure: Evolution of patient inotropes required
timeFrame: 2 - 4 hours and 24 hours of life
measure: Inhaled nitric oxide (NOi) requirement
timeFrame: 2 - 4 hours and 24 hours of life
measure: ventilation requirements on the first day
timeFrame: 2 - 4 hours and 24 hours of life
measure: Oxygenation on the first day
timeFrame: 2 - 4 hours and 24 hours of life
measure: Oxygenation index (OI) on the first day
timeFrame: 2 - 4 hours and 24 hours of life
measure: near-infrared spectroscopy (Nirs) on the first day
timeFrame: 2 - 4 hours and 24 hours of life
measure: B natriuretic peptide (BNP) on the first day
timeFrame: 24 hours of life
measure: PH value on the first day
timeFrame: 6 and 24 hours of life
measure: cardiac malformations
timeFrame: 6 hours of life
measure: Mortality
timeFrame: through study completion, an average of 1 year
measure: Admission to ECMO
timeFrame: through study completion, an average of 1 year
Other outcomes:
measure: maternal age
timeFrame: through study completion, an average of 1 year
measure: maternal history
timeFrame: through study completion, an average of 1 year
measure: baby weight
timeFrame: 30 minutes of life
measure: Patent ductus arteriosus (PAD) on the first day (size)
timeFrame: 6 and 24 hours of life
measure: Patent ductus arteriosus (PAD) on the first day (gradient)
timeFrame: 6 and 24 hours of life
measure: Patent ductus arteriosus (PAD) on the first day (shunt direction)
timeFrame: 6 and 24 hours of life
measure: Patent foramen ovale (PFO) on the first day (shunt direction)
timeFrame: 6 and 24 hours of life
measure: Right ventricle (RV) on the first day diameter
timeFrame: 6 and 24 hours of life
measure: Right ventricle (RV) on the first day TAPSE
timeFrame: 6 and 24 hours of life
measure: Tricuspide Insufitienty
timeFrame: 6 and 24 hours of life
measure: Right ventricle funtion
timeFrame: 6 and 24 hours of life
measure: Left ventricle (LV) on the first day (eccentricity index)
timeFrame: 6 and 24 hours of life
measure: Left ventricle (LV) on the first day (ejection fraction)
timeFrame: 6 and 24 hours of life
measure: Left ventricle (LV) on the first day global funtion
timeFrame: 6 and 24 hours of life
measure: Interventricular septum (IS) on the first day
timeFrame: 6 and 24 hours of life
measure: Pulmonary hypertation grade on the first day
timeFrame: 6 and 24 hours of life
measure: Associated malformations
timeFrame: 24 hours of life
measure: Chromosomopathy or genetic alteration
timeFrame: through study completion, an average of 1 year
measure: Hyperbilirubinemia
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
measure: Early sepsis
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
measure: Omphalitis
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
measure: CDH surgery
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
measure: Surgical classification
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
measure: Days in neonatal intensive care unit (NICU)
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Locations:
city: Buenos Aires
country: Argentina
facility: Hospital de Pediatría S.A.M.I.C. "Prof. Dr. Juan P. Garrahan"
Study officials:
affiliation: Hospital JP Garrahan
name: Mariela Jozefkowicz
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Lefebvre C, Rakza T, Weslinck N, Vaast P, Houfflin-Debarge V, Mur S, Storme L; French CDH Study Group. Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH). Resuscitation. 2017 Nov;120:20-25. doi: 10.1016/j.resuscitation.2017.08.233. Epub 2017 Aug 30.
citation: Duley L, Dorling J, Pushpa-Rajah A, Oddie SJ, Yoxall CW, Schoonakker B, Bradshaw L, Mitchell EJ, Fawke JA; Cord Pilot Trial Collaborative Group. Randomised trial of cord clamping and initial stabilisation at very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2018 Jan;103(1):F6-F14. doi: 10.1136/archdischild-2016-312567. Epub 2017 Sep 18.
citation: Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, Simon WM, Weiner GM, Zaichkin JG. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132(18 Suppl 2):S543-60. doi: 10.1161/CIR.0000000000000267. No abstract available.
citation: Rabe H, Gyte GM, Diaz-Rossello JL, Duley L. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2019 Sep 17;9(9):CD003248. doi: 10.1002/14651858.CD003248.pub4.
citation: Katheria AC, Brown MK, Faksh A, Hassen KO, Rich W, Lazarus D, Steen J, Daneshmand SS, Finer NN. Delayed Cord Clamping in Newborns Born at Term at Risk for Resuscitation: A Feasibility Randomized Clinical Trial. J Pediatr. 2017 Aug;187:313-317.e1. doi: 10.1016/j.jpeds.2017.04.033. Epub 2017 May 16.
citation: McGillick EV, Davies IM, Hooper SB, Kerr LT, Thio M, DeKoninck P, Yamaoka S, Hodges R, Rodgers KA, Zahra VA, Moxham AM, Kashyap AJ, Crossley KJ. Effect of lung hypoplasia on the cardiorespiratory transition in newborn lambs. J Appl Physiol (1985). 2019 Aug 1;127(2):568-578. doi: 10.1152/japplphysiol.00760.2018. Epub 2019 Jun 13.
citation: Kashyap AJ, Hodges RJ, Thio M, Rodgers KA, Amberg BJ, McGillick EV, Hooper SB, Crossley KJ, DeKoninck PLJ. Physiologically based cord clamping improves cardiopulmonary haemodynamics in lambs with a diaphragmatic hernia. Arch Dis Child Fetal Neonatal Ed. 2020 Jan;105(1):18-25. doi: 10.1136/archdischild-2019-316906. Epub 2019 May 23.
citation: Sakurai Y, Azarow K, Cutz E, Messineo A, Pearl R, Bohn D. Pulmonary barotrauma in congenital diaphragmatic hernia: a clinicopathological correlation. J Pediatr Surg. 1999 Dec;34(12):1813-7. doi: 10.1016/s0022-3468(99)90319-6.
citation: Foglia EE, Ades A, Hedrick HL, Rintoul N, Munson DA, Moldenhauer J, Gebb J, Serletti B, Chaudhary A, Weinberg DD, Napolitano N, Fraga MV, Ratcliffe SJ. Initiating resuscitation before umbilical cord clamping in infants with congenital diaphragmatic hernia: a pilot feasibility trial. Arch Dis Child Fetal Neonatal Ed. 2020 May;105(3):322-326. doi: 10.1136/archdischild-2019-317477. Epub 2019 Aug 28.
citation: Winter J, Kattwinkel J, Chisholm C, Blackman A, Wilson S, Fairchild K. Ventilation of Preterm Infants during Delayed Cord Clamping (VentFirst): A Pilot Study of Feasibility and Safety. Am J Perinatol. 2017 Jan;34(2):111-116. doi: 10.1055/s-0036-1584521. Epub 2016 Jun 15.
citation: Katheria A, Poeltler D, Durham J, Steen J, Rich W, Arnell K, Maldonado M, Cousins L, Finer N. Neonatal Resuscitation with an Intact Cord: A Randomized Clinical Trial. J Pediatr. 2016 Nov;178:75-80.e3. doi: 10.1016/j.jpeds.2016.07.053. Epub 2016 Aug 26.
citation: Le Duc K, Mur S, Rakza T, Boukhris MR, Rousset C, Vaast P, Westlynk N, Aubry E, Sharma D, Storme L. Efficacy of Intact Cord Resuscitation Compared to Immediate Cord Clamping on Cardiorespiratory Adaptation at Birth in Infants with Isolated Congenital Diaphragmatic Hernia (CHIC). Children (Basel). 2021 Apr 26;8(5):339. doi: 10.3390/children8050339.