Inflammation and Metabolic Acidosis at Birth (AGAIN: AutophaGy AcIdosis Newborn)

Overview

Protection of brain development is a major aim in the Neonatal Intensive Care Unit. Neonatal encephalopathy (NE) occurs in 1.8 to 7.7 infants per 1000 births. Over the last six years, several randomized control trials have demonstrated that therapeutic hypothermia reduces the rate of death or disability at 18 months of age among infants who survived. However, the neurodevelopmental outcome in milder NE not treated with hypothermia remains unclear. A multicenter prospective observational study will be conducted to determine biological changes of mild neonatal encephalopathy who are not recruited for therapeutic hypothermia .

Full Title of Study: “Autophagy, Mitophagy, Inflammation and Plasmatic Concentration of Melatonin in Newborn With Metabolic Acidosis at Birth”

Study Type

  • Study Type: Observational [Patient Registry]
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: December 31, 2019

Detailed Description

It is a prospective observational multicenter study on 50 newborns with mild neonatal encephalopathy and metabolic acidosis at birth not qualified for therapeutic hypothermia compared to healthy controls. Infants with metabolic acidosis at birth and evidence of mild encephalopathy graded according to Sarnat&Sarnat neurological evaluation will be recruited to evaluate plasma concentration of melatonin and levels of Autophagy, mitophagy and inflammation. Plasmatic changes will be compared to: – healthy control – infants with isolated metabolic acidosis at birth and normal neurological evaluation.

Arms, Groups and Cohorts

  • MILD NE
    • gestational age > 35 weeks and weight > 1800 gr Apgar score < 5 at 10 minutes o need for cardiopulmonary resuscitation at 10 minutes or evidence of base excess > 12 mmol/L or pH < 7,0 at initial blood gas analyses evidence of mild encephalopathy graded according to Sarnat&Sarnat neurological evaluation normal amplitude integrated electroencephalography Plasma levels of melatonin, Atg5, Parkin, Pink1, inflammatory cytokines will be evaluated
  • ISOLATED METABOLIC ACIDOSIS
    • gestational age > 35 weeks and weight > 1800 gr evidence of base excess > 12 mmol/L or pH < 7,0 at initial blood gas analyses Normal Sarnat&Sarnat neurological evaluation Plasma levels of melatonin, Atg5, Parkin, Pink1, inflammatory cytokines will be evaluated
  • HEALTY CONTROLS
    • gestational age > 35 weeks and weight > 1800 gr Normal blood pH or base excess Plasma levels of melatonin, Atg5, Parkin, Pink1, inflammatory cytokiness will be evaluated

Clinical Trial Outcome Measures

Primary Measures

  • change from baseline ATG5 Plasma concentration at 7 days of life
    • Time Frame: birth, 72 hours, 7 days of life
    • correlation between metabolic acidosis at birth and Autophagy. ELISA test will be used to measure plasma levels of ATG5

Secondary Measures

  • change from baseline Parkin and Pink1 Plasma concentration at 7 days of life
    • Time Frame: birth, 72 hours, 7 days of life
    • correlation between metabolic acidosis at birth and Mitophagy. ELISA test will be used to measure plasma levels of Parkin and Park1

Participating in This Clinical Trial

Inclusion Criteria

  • gestational age > 35 weeks and weight > 1800 gr – Apgar score < 5 at 10 minutes o need for cardiopulmonary resuscitation at 10 minutes or evidence of base excess > 12 mmol/L or pH < 7,0 at initial blood gas analyses – evidence of mild encephalopathy graded according to Sarnat&Sarnat neurological evaluation – normal amplitude integrated electroencephalography Exclusion Criteria:

  • suspected inborn errors of metabolism – major chromosomal congenital defects

Gender Eligibility: All

Minimum Age: 15 Minutes

Maximum Age: 6 Hours

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University Hospital of Ferrara
  • Collaborator
    • AUSL Romagna Rimini
  • Provider of Information About this Clinical Study
    • Principal Investigator: Anna Tarocco, Medical Doctor, Principal Investigator – University Hospital of Ferrara
  • Overall Official(s)
    • Anna Tarocco, MD, Principal Investigator, University Hospital s. Anna Ferrara
  • Overall Contact(s)
    • Anna Tarocco, MD, +39 0532236014, anna.tarocco@unife.it

References

Alirezaei M, Kemball CC, Whitton JL. Autophagy, inflammation and neurodegenerative disease. Eur J Neurosci. 2011 Jan;33(2):197-204. doi: 10.1111/j.1460-9568.2010.07500.x. Epub 2010 Dec 7.

Wang Q, Lv H, Lu L, Ren P, Li L. Neonatal hypoxic-ischemic encephalopathy: emerging therapeutic strategies based on pathophysiologic phases of the injury. J Matern Fetal Neonatal Med. 2019 Nov;32(21):3685-3692. doi: 10.1080/14767058.2018.1468881. Epub 2018 May 2.

Hassell KJ, Ezzati M, Alonso-Alconada D, Hausenloy DJ, Robertson NJ. New horizons for newborn brain protection: enhancing endogenous neuroprotection. Arch Dis Child Fetal Neonatal Ed. 2015 Nov;100(6):F541-52. doi: 10.1136/archdischild-2014-306284. Epub 2015 Jun 10.

McAdams RM, Juul SE. Neonatal Encephalopathy: Update on Therapeutic Hypothermia and Other Novel Therapeutics. Clin Perinatol. 2016 Sep;43(3):485-500. doi: 10.1016/j.clp.2016.04.007. Epub 2016 Jun 22.

Parikh P, Juul SE. Neuroprotective Strategies in Neonatal Brain Injury. J Pediatr. 2018 Jan;192:22-32. doi: 10.1016/j.jpeds.2017.08.031. Epub 2017 Oct 12. No abstract available.

Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed. 2017 Jul;102(4):F346-F358. doi: 10.1136/archdischild-2015-309639. Epub 2017 Apr 6.

Massaro AN, Wu YW, Bammler TK, Comstock B, Mathur A, McKinstry RC, Chang T, Mayock DE, Mulkey SB, Van Meurs K, Juul S. Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2018 Mar;194:67-75.e1. doi: 10.1016/j.jpeds.2017.10.060.

Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen KA, Mir I, Pappas A, Montaldo P, Thayyil S, Sanchez PJ, Shankaran S, Laptook AR, Sant'Anna G. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2018 Jan;38(1):80-85. doi: 10.1038/jp.2017.164. Epub 2017 Nov 2.

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