Clinical trial NCT04031508: Effect of a Parenteral Emulsion With Omega3 on Neonates With PPHN and CDH
Official title: Effect of a Parenteral Emulsion With LC-PUFA Omega 3 on Clinical Outcomes, Inflammatory and Oxidative Stress Markers in Neonates With Persistent Pulmonary Hypertension Associated With Congenital Diaphragmatic Hernia
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Pulmonary Hypertension of Newborn
Diaphragm Defect
Keywords: PPHN
Diaphragmatic Hernia
omega 3
DHA and EPA
Lead sponsor: Coordinación de Investigación en Salud, Mexico
Sponsor class: OTHER_GOV
Collaborators: name: University of Southampton
name: Universidad Nacional Autonoma de Mexico
First posted: 2019-07-24
Enrollment: 40
Sex: ALL
Minimum age (years): 1
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Use of a parenteral emulsion that is used as routine nutrition for newborns but not evaluated for persistent pulmonary hypertension.
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to evaluate the effect of a parenteral emulsion containing n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in fish oil on clinical outcomes, markers of inflammation and oxidative stress, and pain in neonates with persistent pulmonary hypertension of the newborn (PPHN) compared with those who receive an emulsion containing soy oil and medium-chain triglycerides (MCT) without n-3 LC-PUFA.

Detailed description: Background. Persistent pulmonary hypertension of the newborn (PPHN), is a syndrome characterized by difficulty to provide normal pulmonary vasodilatation at birth or after birth, which may be related to right ventricular dysfunction, congenital diaphragmatic hernia, sepsis, and meconium aspiration. This condition is understudied. PPHN causes pulmonary vascular resistance (PVR) that decreases left pulmonary artery flow (LPA), meaning that blood cannot be oxygenated in the lungs, leading to low oxygen delivery to all organs. Expensive medication along with ventilator support may help, but the latter and PPHN increase the production of the inflammatory mediators such as pro-inflammatory cytokines and markers of oxidative stress, which cause cell toxicity. To treat the hernia, infants undergo corrective surgery, which further increases the production of inflammatory markers and worsens oxidative stress. As a result, the pain of the surgery also worsens the hypoxemia and respiratory insufficiency in the newborn. PPHN is associated with chronic lung disease (CLD). To date, there is no effective treatment for neonates with PPHN, and around one-third of patients may not respond to current management, leading to the death of up to 33% of infants in developed countries. In Mexico, the mortality rate from PPHN may reach 80%, which is an unacceptable outcome at a high cost. Therefore, the prevention or reduction of the severity of PPHN is actively sought.

Previous reports have shown that the n-3 long-chain polyunsaturated fatty acids (LC-PUFA), such as docosahexaenoic acid (DHA) improves the nutritional status and clinical outcomes in septic newborn reduce systemic inflammation and organ dysfunction in newborns who underwent cardiovascular surgery with a shorter stay in the neonatal intensive care unit. In addition, those babies received lower amounts of analgesics. Other authors have shown that n-3 LC-PUFA reduces oxidative stress. In experimental models of PPHN, the EPA and DHA from Omegaven (fish oil) increased pulmonary artery flow and decrease pulmonary vascular resistance. In the current project, it is hypothesized that n-3 LC-PUFA improves clinical outcomes such as decreasing pulmonary vascular pressure and markers of inflammation and oxidative stress in neonates with PPHN. This hypothesis has not been evaluated.

Objective. The purpose of this study is to evaluate the effect of a parenteral emulsion containing n-3 LC-PUFA in fish oil on clinical outcomes, markers of inflammation and oxidative stress, and pain in neonates with PPHN compared with those who receive an emulsion containing soy and medium-chain triglycerides (MCT) without n-3 LC-PUFA.

Methodology. A double-blind clinical trial will be carried out on Mexican newborns diagnosed with PPHN. The control group will receive intravenous nutrition support including a lipid emulsion based on soy oil plus MCT (control group) and the intervention group will receive a lipid emulsion based on soy oil, MCT, olive oil, and fish oil (n-3 LC-PUFA group); both groups will receive a dose of lipid (3 g/kg/d maximum), through total parenteral nutrition (TPN) for at least 7 days.

The effect of n-3 LC-PUFA will be evaluated on:

1. Clinical outcomes, nutritional status, the manifestation of pain
2. Markers of inflammation
3. Oxidative stress markers

To compare the groups, the Exact Fisher´s, Student's t, or U-Mann-Whitney tests will be applied as appropriate. To adjust the effect of n-3 LC-PUFA for confounders such as fatty acid background and medication, Repeated Measures ANOVA and binary logistic regression will be performed.

Eligibility criteria: Inclusion Criteria:

* Plan to administrate TPN for at least 7 days
* Clinical, gasometric, and echocardiographic diagnosis of congenital diaphragmatic hernia.
* Gestational age \>=34 weeks.
* Written informed consent signed by both parents after an explanation of the objectives, procedures and possible risks and benefits of the research, along with the signature of two witnesses

Exclusion Criteria:

* Diagnosis of complex congenital cardiopathy
* Cyanotic congenital cardiology defect
* Insufficiency of the tricuspid valve
* Immunosuppressive disease. HIV has been associated with PPHN and human herpesvirus with vascular remodeling, perivascular macrophages, and lung fibrosis
* Clinical entities that preclude the total parenteral nutrition for one day or longer.
* Presence of profuse and persistent haemorrhage at any level

Elimination criteria

* Parents who withdraw their consent.
* Starting a drug at doses for nonclotting treatment such as heparin, enoxaparin.
* Development of profuse and persistent haemorrhage at any level after receiving vitamin K treatment.

Primary outcomes:
measure: Change on systolic pressure of pulmonary artery
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour, day 7, day 14 and day 21 post-surgery.
measure: Preductal partial pressure of carbon (PaCO2)
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour and day 7 post-surgery.
measure: Change in Preductal and postductal oxygen saturation (SatO2)
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour, day 7, day 14 and day 21 post-surgery.
measure: Inspired fraction of oxygen (FiO2)
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour, day 7, day 14 and day 21 post-surgery.
measure: Growth velocity and Nutritional status
timeFrame: Before surgery (baseline), day 7, day 14 and day 21 post-surgery.
measure: Pain manifestation
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour, day 7, day 14 and day 21 post-surgery.
Secondary outcomes:
measure: Concentration of plasma cytokines as inflammatory markers
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour, and day 7 post-surgery.
measure: Concentration of inflammatory derived-lipid mediators
timeFrame: Before surgery (baseline), 24 hour, 48 hour, 72 hour, and day 7 post-surgery.
measure: Concentration of total free thiols
timeFrame: At study entry, before surgery (2 baselines), and once a day until day 7 after surgery, then at 14 and 21 days-post-surgery.
measure: Concentration of nitrotyrosine
timeFrame: At study entry, before surgery (2 baselines), and once a day until day 7 after surgery, then at 14 and 21 days-post-surgery.
measure: Concentration of the nuclear factor erythroid 2-related factor 2 (Nrf2)
timeFrame: At study entry, before surgery (2 baselines), and once a day until day 7 after surgery, then at 14 and 21 days-post-surgery.
measure: Concentration of Ratio of F2-isoprostanes (F2-isop) and F2-isofurans (F2-isof)
timeFrame: At study entry, before surgery (2 baselines), and once a day until day 7 after surgery, then at 14 and 21 days-post-surgery.
measure: Chronic Lung Disease
timeFrame: At hospital discharge or 56 day-old, at 6 months and one year of age
Other outcomes:
Locations:
city: Mexico
country: Mexico
facility: Unit of Medical Research in Nutrition
state: Ciudad De Mexico
Study officials:
affiliation: Instituto Mexicano del Seguro Social
name: Mariela Bernabe-Garcia, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: