Hypoxic-Ischemic Encephalopathy Therapy Optimization in Neonates for Better Neuroprotection With Inhalative CO2 (HENRIC)

Hypoxic-Ischemic Encephalopathy Therapy Optimization for Better Neuroprotection With Inhalative CO2 in Asphyxiated, Cooled, Mechanically Ventilated Neonates at Risk for Hypocapnia

This is a Phase I, open-label, single center trial to evaluate the feasibility and safety of low concentration CO2 gas mixture (5% CO2 + 95% air) inhalation in asphyxiated, cooled, mechanically ventilated newborns at risk of hypocapnia with The hypothesis is that hypocapnia, which is driven by hyperventilation in the presence of metabolic acidosis, is deleterious to the injured brain and can be safely avoided with low concentration CO2 inhalation.

Study Overview

• Status: Completed
• Conditions: Perinatal Asphyxia; Hypocapnia; Hypoxic-Ischaemic Encephalopathy
• Intervention / Treatment: Other: 5% carbon-dioxide inhalation

Detailed Description

Specific aims:

1. To test the feasibility of low concentration inhalative CO2 gas mixture (5% CO2 + 95% air) administration to achieve a desired range of pCO2 of 40-60 mmHg in asphyxiated, cooled, mechanically ventilated newborns at risk of hypocapnia with moderate to severe hypoxic-ischemic encephalopathy.
2. To test the safety of CO2 gas mixture (5% CO2 + 95% air) inhalation in asphyxiated, cooled, mechanically ventilated newborns at risk of hypocapnia with moderate to severe hypoxic-ischemic encephalopathy.

Term infants (≥ 36 weeks of gestation) will have to be at risk of hypocapnia to be eligible, as defined by a temperature corrected pCO2 ≤ 40 mmHg in blood gas analysis, at any time within six hours of life.

The gas mixture will be administered through patient circuits in conventional ventilators. Administered CO2 level will be closely monitored at the inhalation circuit (constant 5% = 36 mmHg). Blood gas samples will be taken hourly to ensure targeted and tolerable pCO2 levels.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis University, 1st Department of Pediatrics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• At any time within six hours of life the temperature corrected pCO2 is less than or equal to 40 mmHg after the parameters of mechanical ventilation is set according to standard protocol (SIMV+VG 5ml/kg, fr 20/min, PEEP 5 H20cm, Ti 0,35-0,45 sec).
• Moderate hypoxic- ischaemic encephalopathy, fulfilling TOBY criteria (A, B, C).
• ≥ 36. gest. week
• < 6th hours of life
• Hypothermia treatment
• Parental consent form
• Spontaneous breathing
• Endotracheal intubation
• AUC, VUC in place

Exclusion Criteria:

• Major birth defect
• Meconium aspiration syndrome
• Need for combined catecholamine therapy
• FiO2 > 40%
• Htc < 35%
• Acid-base status: pH < 6.8, lactate > 15mM
• Excessive bicarbonate administration during initial stabilization (> 1mmol/kg)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5% carbon-dioxide inhalation; 5% carbon-dioxide will be administered through patient circuits to asphyxiated, cooled, mechanically ventilated newborns at risk for hypocapnia	Other: 5% carbon-dioxide inhalation; 5% CO2 (36 mmHg) and 95% air gas mixture inhalation, for a maximum of 12 hours or until metabolic acidosis recovery occurs as measured by BE > -5 mmol/L in arterial blood gas samples; Other Names: N-Carbogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of time spent in the desired pCO2 range of 40-60 mmHg (temp. corrected) during CO2 inhalation.	3 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of seizures, either detected clinically or by amplitude integrated EEG monitoring	Within one week
Time until the end point of metabolic acidosis (BE > -5 mmol/L)	During CO2 inhalation (max. 12 hours)
Time until the end point of acidosis (pH > 7.25)	During therapeutic hypothermia (max. 72 hours)
Severe hypotension (mean arterial pressure less than 25 mmHg), despite full inotrope support and volume replacement.	During therapeutic hypothermia (max. 72 hours)
Intracranial haemorrhage detected by MRI	Within seven days
Reduction in Lac/NAA ratio on magnetic resonance spectroscopy	Within seven days
Preserved fractional anisotropy measured on diffusion weighted MRI	Within seven days
Death	Within one month

Collaborators and Investigators

• Sponsor: Semmelweis University
• Investigators: Study Director: Miklós Szabó, MD, PhD, Semmelweis University, 1st Department of Pediatrics

Publications and helpful links

General Publications

• Pappas A, Shankaran S, Laptook AR, Langer JC, Bara R, Ehrenkranz RA, Goldberg RN, Das A, Higgins RD, Tyson JE, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2011 May;158(5):752-758.e1. doi: 10.1016/j.jpeds.2010.10.019. Epub 2010 Dec 10.
• Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4;347(1):43-53. doi: 10.1056/NEJMra012457. No abstract available.
• Klinger G, Beyene J, Shah P, Perlman M. Do hyperoxaemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia? Arch Dis Child Fetal Neonatal Ed. 2005 Jan;90(1):F49-52. doi: 10.1136/adc.2003.048785.
• Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854. Erratum In: N Engl J Med. 2010 Mar 18;362(11):1056.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): November 1, 2019

Study Registration Dates

• First Submitted: February 24, 2016
• First Submitted That Met QC Criteria: March 4, 2016
• First Posted (Estimate): March 7, 2016

Study Record Updates

• Last Update Posted (Actual): April 26, 2021
• Last Update Submitted That Met QC Criteria: April 23, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Neuroprotection; Hypocapnia; Hypothermia treatment; Inhaled CO2
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Signs and Symptoms, Respiratory; Death; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypoxia-Ischemia, Brain; Asphyxia; Hypocapnia
• Other Study ID Numbers: 1Ped-AsphHENRIC001

Plan for Individual participant data (IPD)

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