Effect of a Parenteral Emulsion With Omega3 on Neonates With PPHN and CDH (CDH-PPHN-N3)

Coordinación de Investigación en Salud, Mexico

Status and phase: Invitation-only; Phase 2

Conditions: Pulmonary Hypertension of Newborn; Diaphragm Defect

Treatments: Combination Product: lipid injectable emulsion with Fish oil

Study type: Interventional

Funder types: Other

Identifiers

NCT04031508

R-2019-785-044

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 1 hour to 15 days old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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40 participants in 2 patient groups

Omega 3

Experimental group

Description:

The experimental group will receive a parenteral emulsion containing soy oil, MCT, olive oil and n-3 LCPUFA in fish oil

Treatment:

Combination Product: lipid injectable emulsion with Fish oil

Control group

Sham Comparator group

Description:

The Control group will receive a parenteral emulsion containing soy oil and MCT

Treatment:

Combination Product: lipid injectable emulsion with Fish oil