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

Abstract

Background: 2-8% 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.

Methods: The 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.

Prospect: The 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 registration: ClinicalTrials.gov identifier: NCT01370044.

Figures

Figure 1

The application device. (A) Low-pressure can containing 6 liter of the study medication with attached, loosely fitting, “one-size for all” respiratory mask. Pressing on the grey cantilever initiates the gas flow. (B) Application of the study medication to a child. The parents are advised to press on the grey cantilever until the audible gas-flow has stopped (after ≈3 minutes).

Figure 2

Experimental setting. Assessment of inspiratory & endtidal pCO2, respiratory volume & rates, air flow velocity & pressure was done using an artificial lung, a pCO2-sensor, a pneumotychograph, and an anatomical facsimile of a face with nasopharynx and oral cavity of a 2 year-old child. Accordingly, anatomical dead space was adjusted to 40 ml.

Figure 3

Inspiratory and endtidal pCO2 concentrations. (A-B) Course of the inspiratory and endtidal pCO2 using the experimental setting described in Figure 2. The gas flow was started after 50 seconds and continued for 60 seconds. The experiment was repeated with two different respiratory rates and tidal volumes: (A) 30/min | 90 ml (corresponding to 2-year-old child) and (B) 40/min | 65 ml (corresponding to a 9-months-old infant). In both cases we observed an increase of the inspiratory pCO2 by a maximum of ≈20 mmHg. (C-D)In vivo respiration of 6 liter CO2 over 3 minutes: the gas flow was again started at 50 seconds. The panels depict two different experimental conditions: (C) The test person tried to maintain a respiratory rate of 40/min in synchrony with a metronome over the entire period. Under these conditions the endtidal pCO2 rose by 7 mmHg. In setting (D) the test person had hyperventilated before the start of the gas flow. Starting from a lower pCO2 of 17 mmHg, the pCO2 again rose by 7 mmHg.

Figure 4

Flow diagram of the CARDIF-trial.