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

Autophagy, Mitophagy, Inflammation and Plasmatic Concentration of Melatonin in Newborn With Metabolic Acidosis at Birth

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 .

Study Overview

• Status: Unknown
• Conditions: Inflammation; Neonatal Encephalopathy; Metabolic Acidosis; Cell Damage

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.

• Study Type: Observational
• Enrollment (Anticipated): 150

Contacts and Locations

• Study Contact: Name: Anna Tarocco, MD; Phone Number: +39 0532236014; Email: anna.tarocco@unife.it
• Study Contact Backup: Name: Paolo Pinton, Prof; Phone Number: 0532455802; Email: paolo.pinton@unife.it

Study Locations

• Italy
  • Ferrara, Italy, 44124
    • Recruiting
    • University Hospital "Sant'Anna" of Ferrara
  • Rimini, Italy, 47923
    • Recruiting
    • Infermi Hospital Rimini

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 minutes to 6 hours (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

will be recruited 50 newborns with mild neonatal encephalopathy and metabolic acidosis at birth not qualified for therapeutic hypothermia

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change from baseline Parkin and Pink1 Plasma concentration at 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	birth, 72 hours, 7 days of life

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
change from baseline Plasma Concentration of Melatonin at 7 days of life	UPLC-Massa Acquity-Xevo TQD (Waters) will be used to measure plasma melatonin concentration.	birth, 72 hours, 7 days of life
change from baseline of inflammatory cytokines at 7 days of life	correlation between metabolic acidosis at birth and inflammatory cytokines. ELISA test will be used to measure plasma levels inflammatory cytokines.	birth, 72 hours, 7 days of life

Collaborators and Investigators

• Sponsor: University Hospital of Ferrara
• Collaborators: AUSL Romagna Rimini
• Investigators: Principal Investigator: Anna Tarocco, MD, University Hospital s. Anna Ferrara

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• Tarocco A, Morciano G, Perrone M, Cafolla C, Ferre C, Vacca T, Pistocchi G, Meneghin F, Cocchi I, Lista G, Cetin I, Greco P, Garani G, Stella M, Natile M, Ancora G, Savarese I, Campi F, Bersani I, Dotta A, Tiberi E, Vento G, Chiodin E, Staffler A, Maranella E, Di Fabio S, Wieckowski MR, Giorgi C, Pinton P. Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic-ischemic encephalopathy. Sci Rep. 2022 May 12;12(1):7795. doi: 10.1038/s41598-022-11870-w.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2019
• Primary Completion (ACTUAL): December 31, 2019
• Study Completion (ANTICIPATED): December 31, 2020

Study Registration Dates

• First Submitted: March 27, 2019
• First Submitted That Met QC Criteria: March 29, 2019
• First Posted (ACTUAL): April 1, 2019

Study Record Updates

• Last Update Posted (ACTUAL): March 25, 2020
• Last Update Submitted That Met QC Criteria: March 24, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: inflammation; Autophagy; metabolic acidosis; birth asphyxia; mild neonatal encephalopathy; Mitophagy
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Acid-Base Imbalance; Inflammation; Brain Diseases; Acidosis
• Other Study ID Numbers: 639/2018/Sper/AOUFe

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No