CO2 Chemosensitivity Testing for SUDEP Risk in Epilepsy

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Iowa

Must not be taking: Opioids

Disqualifiers: Uncontrolled cardiac, pulmonary, hepatic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

335 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to understand the causes of Sudden Unexpected Death in Epilepsy (SUDEP) by examining how seizures affect breathing, heart health, and arousal. It includes breathing tests using a special gas mixture (6% carbon dioxide/50% oxygen/balance nitrogen) to determine if people with epilepsy have difficulty waking up or sensing high carbon dioxide levels after seizures. Researchers will follow participants for ten years to monitor their ongoing health. This trial may suit individuals with diagnosed or suspected epilepsy receiving care at the University of Iowa Health Care Epilepsy Clinic. As an unphased study, it offers a unique opportunity to contribute to groundbreaking research that could enhance understanding and care for epilepsy patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude people who are currently using opioids.

What prior data suggests that this respiratory physiology testing is safe for epilepsy patients?

Research has shown that a gas mixture containing 6% carbon dioxide, 50% oxygen, and nitrogen can affect breathing and heart rate. Studies use this mixture to observe reactions to elevated carbon dioxide levels. The goal is to understand the body's response, particularly in individuals with epilepsy, to gain insights into the risk of Sudden Unexpected Death in Epilepsy (SUDEP).

Although this gas mixture is not flammable, it requires careful handling. Stored under pressure, it could explode if heated. Some participants may experience faster breathing and heart rate as their bodies respond to the carbon dioxide. These reactions are expected and are part of the study to understand how the body manages them.

The mixture is used in a controlled environment with safety measures in place. Those interested in participating in such studies should discuss potential risks and benefits with the research team to make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the CO2 chemosensitivity testing for SUDEP risk in epilepsy because it explores a novel way of understanding how respiratory responses might be linked to seizure activity. Unlike typical treatments that focus on controlling seizures with medications like antiepileptic drugs, this approach investigates the body's reaction to a specific gas mixture, which includes 6% carbon dioxide, 50% oxygen, and a balance of nitrogen. This method could reveal new insights into how breathing patterns and gas sensitivity relate to sudden unexpected death in epilepsy (SUDEP), potentially leading to improved risk assessment and preventive strategies.

What evidence suggests that this respiratory physiology testing is effective for understanding SUDEP risk in epilepsy?

In this trial, participants will undergo respiratory physiology testing using a mix of 6% carbon dioxide and 50% oxygen. Research has shown that this gas mixture can influence breathing and heart functions, aiding in testing reactions to higher carbon dioxide levels, which is crucial for understanding breathing problems. The mixture widens blood vessels, affecting heart function. Studies have found that this gas mixture helps monitor the body's response to changes in breathing and blood flow. This information is valuable for studying conditions like SUDEP, where breathing issues might contribute. ^{1 6 7 8 9}

Who Is on the Research Team?

Brian Gehlbach, MD

Principal Investigator

University of Iowa

George Richerson, MD, PhD

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

This trial is for adults aged 18-99 with confirmed or suspected epilepsy, either admitted to the Epilepsy Monitoring Unit (EMU) or receiving care at the University of Iowa Health Care Epilepsy Clinic. It's not suitable for those with uncontrolled heart, lung, liver diseases, progressive neurological conditions not related to epilepsy, current opioid users, pregnant women or those who could become pregnant without effective birth control.

Inclusion Criteria

Admission to the EMU for spell characterization (EMU group) or undergoing care in the University of Iowa Health Care Epilepsy Clinic

I have epilepsy.

Exclusion Criteria

I am a woman who could become pregnant and have not used effective birth control recently.

I do not have any uncontrolled heart, lung, or liver diseases.

I have difficulty making decisions and do not have someone to help me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Hospital Admission and Initial Testing

Participants undergo continuous VideoEEG, ECG, and noninvasive cardiorespiratory monitoring during their stay in the Epilepsy Monitoring Unit (EMU) to correlate heart rate and breathing patterns with EEG patterns related to seizures.

5 days

Inpatient stay

Outpatient Testing

Participants undergo repeat HCVR testing up to 4 times over 2 years, with some tests occurring 30 minutes, 2 hours, and 18 hours after seizures.

2 years

4 visits (in-person)

Long-term Follow-up

Participants are monitored annually for ten years through interviews and questionnaires to assess health and ascertain any occurrences of SUDEP.

10 years

Annual interviews (in-person or virtual)

What Are the Treatments Tested in This Trial?

Interventions

• 6% Carbon dioxide/50% oxygen/balance nitrogen mixture

Trial Overview The study aims to understand what causes Sudden Unexpected Death in Epilepsy (SUDEP) by examining how seizures affect breathing and arousal. Participants will inhale a special gas mixture containing carbon dioxide and oxygen while their health is monitored over ten years.

How Is the Trial Designed?

Group I: Respiratory physiology testing Experimental Treatment 1 Intervention

Subjects will wear a nosepiece and breathe through a Y-valve that allows switching from room air to two 5-liter rebreathing bags pre-filled with 50% O2, 6% CO2, and balance N2. Ventilation and respiratory gases will be measured using a pneumotachograph and rapid gas analyzers (Ultima PFX pulmonary function/stress testing system, Medical Graphics Corp). In subjects who experience clinical seizure-like activity, we will repeat the HCVR. This repeat test will occur 2 or more hours after a generalized convulsive seizure (GCS). We will repeat the HCVR at least 30 minutes after a non-GCS. Finally, we may repeat the HCVR at least 18 hours after the last seizure (GCS or non-GCS). It is anticipated that some subjects may exhibit frequent seizures that necessitate the adjustment of this schedule. Subjects may also be asked to sniff, hold their breath, and breathe through tubes of different sizes.

Who Is Running the Clinical Trial?

University of Iowa

Lead Sponsor

Trials

486

Recruited

934,000+

Published Research Related to This Trial

Inhaled 5% carbon dioxide/95% oxygen was well tolerated by all six children with non-convulsive status epilepticus (NCSE) during a 120-second treatment, with no significant adverse effects or changes in blood gas levels observed.

Despite being well tolerated, the treatment showed limited and transient effects on EEG normalization and did not result in any clinical improvements, indicating that its efficacy as an anticonvulsant in this context is questionable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5% Carbon Dioxide is safe but of limited efficacy as a treatment for paediatric non-convulsive status epilepticus: An open label observational study. Forsyth, R., Martland, T., Lai, M., et al.[2018]

The study measured the hypercapnic ventilatory response (HCVR) in 68 epilepsy patients, finding that a low HCVR is associated with a higher risk of prolonged postictal hypercapnia after generalized convulsive seizures (GCSs), which may increase the risk of severe respiratory depression and sudden unexpected death in epilepsy (SUDEP).

The HCVR measurement was safe and well-tolerated, indicating it can be a useful bedside tool in epilepsy monitoring units to identify patients at greater risk for respiratory complications following seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ventilatory response to CO2 in patients with epilepsy. Sainju, RK., Dragon, DN., Winnike, HB., et al.[2021]

In a study involving rats with implanted EEG electrodes, carbamazepine showed a dose-related protective effect against seizures induced by hyperbaric oxygen exposure, while ethosuximide did not provide any protection.

The findings suggest that carbamazepine could be an effective preventive treatment for oxygen-induced seizures during hyperbaric oxygen therapy, highlighting its potential role in enhancing safety during such treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of carbamazepine and ethosuximide on hyperoxic seizures. Reshef, A., Bitterman, N., Kerem, D.[2019]

Postconvulsive central apnea (PCCA) was observed in 22.1% of generalized convulsive seizures (GCS) and may serve as a clinical biomarker for sudden unexpected death in epilepsy (SUDEP), particularly since it was present in cases of near-SUDEP and one probable SUDEP case.

Postictal hypoxemia occurred in 86% of GCS, but early administration of oxygen significantly improved recovery of oxygen saturation levels, highlighting the importance of timely oxygen therapy in managing postictal hypoxemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers for SUDEP: Are We There Yet? King-Stephens, D.[2020]

Individuals with epilepsy (PWE) showed greater brainstem BOLD activations during hypercapnic breathing challenges compared to healthy controls (HC), particularly in the dorsal raphe, suggesting abnormal chemosensing related to respiratory control.

PWE exhibited increased connectivity between brainstem structures during hypercapnia, indicating potential dysfunction in respiratory regulation that could contribute to the risk of sudden unexpected death in epilepsy (SUDEP).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional MRI Correlates of Carbon Dioxide Chemosensing in Persons With Epilepsy. Hampson, JP., Lacuey, N., Rani, MS., et al.[2023]

A case study of a combat diving candidate revealed unexpected symptoms of central nervous system oxygen toxicity (CNS-OT) while breathing pure oxygen with elevated carbon dioxide levels, highlighting the risks associated with hypercapnia during diving.

Despite the candidate exhibiting signs like severe headache, nausea, and facial muscle twitching, further medical examinations showed no neurological abnormalities, indicating that CNS-OT can occur even under controlled conditions, which has not been previously documented in literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptoms of central nervous system oxygen toxicity during 100% oxygen breathing at normobaric pressure with increasing inspired levels of carbon dioxide: a case report. Eynan, M., Arieli, Y., Taran, B., et al.[2021]

A case study of a patient with temporal lobe epilepsy revealed that focal seizures can lead to significant central apnea and oxygen desaturation, highlighting a potential risk factor for sudden unexpected death in epilepsy (SUDEP).

The patient's death from SUDEP occurred without any convulsive activity, suggesting that ictal hypoxia can happen in non-convulsive seizures, emphasizing the need for awareness of this risk in epilepsy management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ictal central apnea as a predictor for sudden unexpected death in epilepsy. Schuele, SU., Afshari, M., Afshari, ZS., et al.[2011]

In a study involving 20 female Long-Evans rats, the activation of oxygen-conserving reflexes (OCRs) during seizures led to sudden death in 18 of the rats, mimicking physiological conditions observed in human cases of sudden unexpected death in epilepsy (SUDEP).

The study found that terminal central apnea and significant drops in mean arterial pressure preceded death, indicating that the induced reflexes during seizures can cause fatal outcomes, while nonseizing control rats did not experience fatal effects from similar reflex activations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ictal activation of oxygen-conserving reflexes as a mechanism for sudden death in epilepsy. Biggs, EN., Budde, R., Jefferys, JGR., et al.[2023]

In a study of 33 patients with localization-related epilepsy, significant increases in end-tidal CO₂ (ETCO₂) were observed during and after seizures, indicating severe respiratory disturbances that could contribute to the risk of sudden unexpected death in epilepsy (SUDEP).

The study found that while there were prolonged increases in ETCO₂ levels, postictal respiratory effort was not impaired, suggesting that ictal hypoxemia may be linked to ventilation-perfusion mismatch rather than direct respiratory failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respiratory changes with seizures in localization-related epilepsy: analysis of periictal hypercapnia and airflow patterns. Seyal, M., Bateman, LM., Albertson, TE., et al.[2010]

In a review of seven seizure cases among five patients undergoing hyperbaric oxygen therapy, all patients had pre-existing medical conditions or were on medications that could lower their seizure threshold, such as chronic obstructive pulmonary disease and narcotic withdrawal.

The findings suggest that patients with certain risk factors, including specific medications and medical comorbidities, may be more susceptible to oxygen toxicity seizures during hyperbaric oxygen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions. Seidel, R., Carroll, C., Thompson, D., et al.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04134754

Carbon Dioxide (CO2) Chemosensitivity and SUDEP ... One test, called the hypercapnic ventilatory response (HCVR), will have you rebreathe a gas mixture of 6% carbon dioxide and 50% oxygen to look at how more you ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4794276/

Regulation of Breathing and Autonomic Outflows by ... The cardiovascular effects of hypercapnia result from effects of CO2 at multiple levels (264, 438). CO2 dilates the peripheral vasculature which tends to lower ...

3. apps.dtic.mil apps.dtic.mil/sti/tr/pdf/ADA237813.pdf

Effectiveness of Oxygen-Nitrogen Gas Mixtures in ... - DTIC The six gas mixtures were administered using a doubtle blind experimental design. The 93.80%N2 6.20/0 gas mixture was determined to have practical application ...

4. adc-int.org adc-int.org/files/ADCI%20Consensus%20Standards%206_2_25.pdf

international consensus standards for commercial diving ... • Maintain proper atmosphere (e.g., correct levels of oxygen, carbon dioxide and other gasses) and pressure in the saturation complex ... has an oxygen mixture ...

5. researchgate.net researchgate.net/publication/263296330_Effects_of_elevated_oxygen_and_carbon_dioxide_partial_pressures_on_respiratory_function_and_cognitive_performance

Effects of elevated oxygen and carbon dioxide partial ... Hyperoxia during diving has been suggested to exacerbate hypercapnic narcosis and promote unconsciousness. We tested this hypothesis in male ...

6. airgas.com airgas.com/msds/014596.pdf

Oxidizing Gas Mixture: Carbon Dioxide / Nitrogen / Oxygen Signal word. : Danger. Hazard statements. : May cause or intensify fire; oxidizer. Contains gas under pressure; may explode if heated. May increase respiration ...

7. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2beca3c8-c5b3-6e37-e063-6394a90a3497

Label: CARBON DIOXIDE-OXYGEN-NITROGEN MIXTURE gas MAY INCREASE RESPIRATION AND HEART RATE. Do not handle until all safety precautions have been read and understood. Keep and store away from clothing and other ...

8. airgas.com airgas.com/msds/002061.pdf

SAFETY DATA SHEET Nonflammable Gas Mixture: Carbon Dioxide / Nitrogen / Oxygen. Not available. Gas. SAFETY DATA SHEET. GHS product identifier. Other means of identification.

9. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bec46ff-7f15-fdb2-e063-6294a90af0e8

Label: CARBON DIOXIDE-OXYGEN-NITROGEN MIXTURE gas Rx only. WARNING: Administration of this gas mixture may be hazardous or contraindicated. ... WARNING: CONTAINS GAS UNDER PRESSURE; MAY EXPLODE IF HEATED. MAY ...