Clinical trial NCT02700854: Hypoxic-Ischemic Encephalopathy Therapy Optimization in Neonates for Better Neuroprotection With Inhalative CO2
Official title: Hypoxic-Ischemic Encephalopathy Therapy Optimization for Better Neuroprotection With Inhalative CO2 in Asphyxiated, Cooled, Mechanically Ventilated Neonates at Risk for Hypocapnia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypoxic-Ischaemic Encephalopathy
Perinatal Asphyxia
Hypocapnia
Keywords: Hypothermia treatment
Hypocapnia
Inhaled CO2
Neuroprotection
Lead sponsor: Semmelweis University
Sponsor class: OTHER
First posted: 2016-03-07
Enrollment: 10
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of time spent in the desired pCO2 range of 40-60 mmHg (temp. corrected) during CO2 inhalation.
timeFrame: 3 days
Secondary outcomes:
measure: Number of seizures, either detected clinically or by amplitude integrated EEG monitoring
timeFrame: Within one week
measure: Time until the end point of metabolic acidosis (BE > -5 mmol/L)
timeFrame: During CO2 inhalation (max. 12 hours)
measure: Time until the end point of acidosis (pH > 7.25)
timeFrame: During therapeutic hypothermia (max. 72 hours)
measure: Severe hypotension (mean arterial pressure less than 25 mmHg), despite full inotrope support and volume replacement.
timeFrame: During therapeutic hypothermia (max. 72 hours)
measure: Intracranial haemorrhage detected by MRI
timeFrame: Within seven days
measure: Reduction in Lac/NAA ratio on magnetic resonance spectroscopy
timeFrame: Within seven days
measure: Preserved fractional anisotropy measured on diffusion weighted MRI
timeFrame: Within seven days
measure: Death
timeFrame: Within one month
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Semmelweis University, 1st Department of Pediatrics
Study officials:
affiliation: Semmelweis University, 1st Department of Pediatrics
name: Miklós Szabó, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4;347(1):43-53. doi: 10.1056/NEJMra012457. No abstract available.
citation: 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.
citation: 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.
citation: 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.