CARbon DIoxide for the treatment of Febrile seizures: rationale, feasibility, and design of the CARDIF-study

Abstract

Background2-8% of all children aged between 6 months and 5 years have febrile seizures. Often these seizures cease spontaneously, however depending on different national guidelines, 20-40% of the patients would need therapeutic intervention. For seizures longer than 3-5 minutes application of rectal diazepam, buccal midazolam or sublingual lorazepam is recommended. Benzodiazepines may be ineffective in some patients or cause prolonged sedation and fatigue. Preclinical investigations in a rat model provided evidence that febrile seizures may be triggered by respiratory alkalosis, which was subsequently confirmed by a retrospective clinical observation. Further, individual therapeutic interventions demonstrated that a pCO2-elevation via re-breathing or inhalation of 5% CO2 instantly stopped the febrile seizures. Here, we present the protocol for an interventional clinical trial to test the hypothesis that the application of 5% CO2 is effective and safe to suppress febrile seizures in children.MethodsThe CARDIF (CARbon DIoxide against Febrile seizures) trial is a monocentric, prospective, double-blind, placebo-controlled, randomized study. A total of 288 patients with a life history of at least one febrile seizure will be randomized to receive either carbogen (5% CO2 plus 95% O2) or placebo (100% O2). As recurrences of febrile seizures mainly occur at home, the study medication will be administered by the parents through a low-pressure can fitted with a respiratory mask. The primary outcome measure is the efficacy of carbogen to interrupt febrile seizures. As secondary outcome parameters we assess safety, practicability to use the can, quality of life, contentedness, anxiousness and mobility of the parents.ProspectThe CARDIF trial has the potential to develop a new therapy for the suppression of febrile seizures by redressing the normal physiological state. This would offer an alternative to the currently suggested treatment with benzodiazepines. This study is an example of academic translational research from the study of animal physiology to a new therapy.Trial registrationClinicalTrials.gov identifier: NCT01370044

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“…A clinical study found that hypercapnic hyperventilation, induced by insertion of additional airway dead space to keep the end-tidal carbon dioxide pressure close to 55 mmHg during hyperventilation, shortens the emergence time from isoflurane anesthesia [47]. Another study of children with febrile seizures showed that 5% carbon dioxide plus 95% oxygen was effective and safe for suppressing febrile seizures in children [48]. Thus, short-term exposed to a low concentration of inhaled carbon dioxide is a safe strategy for clinical application.…”

Hypoxia and its therapeutic possibilities in paediatric cancers

“…37,77 Despite some reports of breathing discomfort alongside carbogen inhalation, compliance in adults is high; 78 in children, carbogen inhalation per se is reported to be safe and feasible without any significant compliance issues. [79][80][81] It is, however, foreseeable that this therapy would be more suitable for older children, or toddlers and babies that have already been sedated for radiotherapy. In a clinical trial that combined carbogen inhalation with radiotherapy for the treatment of high-grade paediatric gliomas, no increase in survival over radiotherapy alone was noted.…”