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

Study Overview
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Brief Summary
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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.

Detailed Description
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Specific aims: 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. 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.

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

Conditions
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Hypoxic-Ischaemic Encephalopathy, Perinatal Asphyxia, Hypocapnia

Intervention / Treatment
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* Other: 5% carbon-dioxide inhalation


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5% carbon-dioxide inhalation<br>5% carbon-dioxide will be administered through patient circuits to asphyxiated, cooled, mechanically ventilated newborns at risk for hypocapnia | Other: 5% carbon-dioxide inhalation<br>* 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<br>* Other names: N-Carbogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypothermia treatment, Hypocapnia, Inhaled CO2, Neuroprotection