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Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO2: the HENRIC feasibility and safety trial.

ABSTRACT: BACKGROUND:There is an association between hypocapnia and adverse neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our aim was to test the safety and feasibility of 5% CO2 and 95% air inhalation to correct hypocapnia in mechanically ventilated infants with NE undergoing therapeutic hypothermia. METHODS:Ten infants were assigned to this open-label, single-center trial. The gas mixture of 5% CO2 and 95% air was administered through patient circuits if the temperature-corrected PCO2 ?40?mm?Hg. The CO2 inhalation was continued for 12?h or was stopped earlier if the base deficit (BD) level decreased <5?mmol/L. Follow-up was performed using Bayley Scales of Infant Development II. RESULTS:The patients spent a median 95.1% (range 44.6-98.5%) of time in the desired PCO2 range (40-60?mm?Hg) during the inhalation. All PCO2 values were >40?mm?Hg, the lower value of the target range. Regression modeling revealed that BD and lactate had a tendency to decrease during the intervention (by 0.61 and 0.55?mmol/L/h, respectively), whereas pH remained stable. The rate of moderate disabilities and normal outcome was 50%. CONCLUSIONS:Our results suggest that inhaled 5% CO2 administration is a feasible and safe intervention for correcting hypocapnia.

SUBMITTER: Szakmar E

PROVIDER: S-EPMC7223064 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO<sub>2</sub>: the HENRIC feasibility and safety trial.

Szakmar Eniko E Kovacs Kata K Meder Unoke U Bokodi Geza G Andorka Csilla C Lakatos Andrea A Szabo Attila J AJ Belteki Gusztav G Szabo Miklos M Jermendy Agnes A

Pediatric research 20191130 6

<h4>Background</h4>There is an association between hypocapnia and adverse neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our aim was to test the safety and feasibility of 5% CO<sub>2</sub> and 95% air inhalation to correct hypocapnia in mechanically ventilated infants with NE undergoing therapeutic hypothermia.<h4>Methods</h4>Ten infants were assigned to this open-label, single-center trial. The gas mixture of 5% CO<sub>2</sub> and 95% air was administered through patie ...[more]

PMID: 31785594

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Project description:Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44-53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known: • Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy. • Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New: • Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia. • There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

Project description:A growing body of evidence suggests that memories of fearful events may be altered after initial acquisition or learning. Although much of this work has been done in rodents using Pavlovian fear conditioning, it may have important implications for fear memories in humans such as in post-traumatic stress disorder (PTSD). A recent study suggested that cued fear memories, made labile by memory retrieval, were made additionally labile and thus more vulnerable to subsequent modification when mice inhaled 10% carbon dioxide (CO2) during retrieval. In light of this finding, we hypothesized that 10% CO2 inhalation soon after fear acquisition might affect memory recall 24 h later. We found that both cue and context fear memory were increased by CO2 exposure after fear acquisition. The effect of CO2 was time-dependent, as CO2 inhalation administered 1 or 4 h after cued fear acquisition increased fear memory, whereas CO2 inhalation 4 h before or 24 h after cued fear acquisition did not increase fear memory. The ability of CO2 exposure following acquisition to enhance fear memory was not a general consequence of stress, as restraining mice after acquisition did not alter cued fear memory. The memory-enhancing action of CO2 may be relatively specific to fear conditioning as novel object recognition was impaired by post-training CO2 inhalation. To explore the molecular underpinnings of these effects, we tested if they depended on the acid-sensing ion channel-1a (ASIC1A), a proton-gated cation channel that mediates other effects of CO2, likely via its ability to sense acidosis induced during CO2 inhalation. We found that CO2 inhalation did not alter cued or context fear memory in Asic1a-/- mice, suggesting that this phenomenon critically depends on ASIC1A. These results suggest that brain acidosis around the time of a traumatic event may enhance memory of the trauma, and may thus constitute an important risk factor for developing PTSD. Moreover, preventing peritraumatic acidosis might reduce risk of PTSD.

Dataset Information

Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO2: the HENRIC feasibility and safety trial.

Publications

Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO<sub>2</sub>: the HENRIC feasibility and safety trial.

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