Abstract
BACKGROUND: Drug-resistant epilepsy (DRE) affects nearly one-third of patients and remains a major unmet clinical need, despite advances in anti-seizure medications (ASMs). Carbogen, a low-concentration carbon dioxide (CO(2)) and oxygen (O(2)) gas mixture, has reemerged as a physiology-based therapy owing to renewed insights into pH-sensitive seizure mechanisms. METHODS: This review summarizes preclinical and clinical evidence on carbogen inhalation for seizure control. Mechanistic data on pH-dependent ion channels, GABAergic inhibition, and adenosine signaling were condensed, and clinical outcomes across seizure types and inhalation protocols were compared for safety and efficacy. RESULTS: Carbogen induces short-term respiratory acidosis, lowering brain extracellular pH to activate acid-sensitive ion channels (e.g., ASIC1a and NaV1.2), enhance GABAergic inhibition, and boost adenosine signaling. These effects are rapid, reversible, and distinct from conventional ASMs. Preclinical studies show strong seizure suppression, especially under hyperventilation-induced alkalosis. Clinically, brief low-dose inhalation (5% CO(2) for ≤ 3 min) is effective and well tolerated in focal and absence seizures, whereas earlier high-concentration protocols caused adverse effects. Efficacy varies by seizure type: benefits in nonconvulsive status epilepticus (NCSE) are limited, and the CARDIF trial found no advantage for pediatric febrile seizures. Ongoing work, such as the CRESCENT trial, is exploring carbogen as an adjunct therapy for pediatric convulsive status epilepticus (CSE). CONCLUSIONS: Evidence supports carbogen's therapeutic promise and highlights the need for precise patient selection, controlled delivery, and comprehensive safety testing. Future research should develop biomarker-guided, closed-loop systems and test synergy with established ASMs to advance carbogen as a mechanism-based therapy within precision epilepsy care.