Carbogen for status epilepticus in children trial

Plain English Summary

Background and study aims
An epileptic seizure that is not stopping is a medical emergency. The longer it lasts the greater the risk of brain damage or even, occasionally, death. We need better ways to stop long seizures sooner. We believe creating a slightly more acidic environment within the brain may help this. One convenient and safe way to alter brain acidity is to give someone a different gas mixture to breathe. Our bodies take oxygen out of the air we breathe in; we then breathe out carbon dioxide as a “waste” gas. Carbon dioxide is very slightly acidic: if you mix a small amount (5%) with oxygen it makes the body and brain slightly acidic. This mixture is called Carbogen. It still has much more oxygen in it than room air (95% compared to 21%), and only the same amount of carbon dioxide as in the air we normally breathe out.

Who can participate?
Children with ongoing seizures.

What does the study involve?
Half the children will receive standard drug treatment whilst breathing 100% oxygen (which is what happens currently) and the other half will receive standard drug treatment whilst inhaling Carbogen. The choice of whether a child is given Oxygen or Carbogen will be random. All children will receive the same standard medical drug treatment for their seizure.
Because this is an emergency situation, there isn’t time to give children's families information about the trial or ask if they wish to take part before the treatment is given. Families will be told that their child was in the trial and will be asked for their consent to remain in the study. This is known as “deferred consent”. We have recently successfully completed a trial of another treatment of ongoing seizures this way and found families understood and accepted this.

What are the possible benefits and risks of participating?
Benefits:
As most medicines used in the treatment of Chronic Status Epilepticus (CSE) have sedating (induces a state of calm or sleep) or anaesthetic (reduces sensitivity to pain) properties, breathing complications are common. In contrast, Carbogen is non-sedating, and may actually act to stimulate breathing. The effects of Carbogen are potentially both rapidly acting and rapidly reversible. Whilst there has been no long-term benefit currently observed in the use of Carbogen in preventing seizures from occurring in the future, use of Carbogen during an ongoing seizure may help to stop the seizure quicker.

Risks:
The direct burden of participation will be minimal. The experience of the trial intervention is identical to standard care (inhaling a medical gas via facemask alongside standard medical care). Since by definition children are in an ongoing seizure their awareness of involvement will be very limited if any. There are no additional visits, blood tests or other investigations arising from trial participation beyond standard care: all follow-up is based on data extraction from hospital notes.
Inhalation of much higher proportions of carbon dioxide in air than are being used here (20-30%) in awake volunteers causes a distressing sense of panic and “air hunger” that rapidly and immediately ends upon discontinuation. However we and others have shown that inhalation of 5% carbon dioxide is well tolerated by awake children. Again because these children are in a seizure they are unlikely to have any subjective sense of breathlessness.
Increasing the proportion of carbon dioxide in inhaled air will cause very slight increases in blood flow and pressure in the brain: they are equivalent to those that occur if someone holds their breath, which causes carbon dioxide levels in the blood to rise by similar amounts. They are dwarfed by the effects on blood flow and pressure of the seizure itself.
There are two conditions that in an emergency setting are sometimes mistaken for and treated as prolonged epileptic seizures: these are (i) non-epileptic attack disorder (NEAD) where someone erroneously believes they are having a seizure and imitates its features, sometimes as a result of emotional or psychological distress and (ii) a rare situation where critically ill unconscious patients can exhibit unusual sustained stiff postures.
Treating the NEAD group for epileptic seizures is not inherently dangerous but exposes patients to medications and procedures unnecessarily and potentially entrenches an erroneous diagnosis of epilepsy. Treating the second group for epileptic seizures can be harmful because in general causing further sedation and depressing breathing effort (which is a common side effect of medications for epilepsy) can make this situation worse. We have carefully considered any possible additional risk to patients in this second group from receiving carbogen (i.e. any additional risk from being in the active rather than the treatment-as-usual arm of the trial) and believe these are acceptable. However we have incorporated specific training for participating sites to make them aware of these two conditions and to improve diagnostic assessment skills in this difficult, emergency situation. Generally this second condition is not hard to suspect or diagnosis: the issue is awareness of the existence of the phenomenon. By offering specific site training we will be improving care for this rare clinical situation generally.
For parents there may be some anxiety resulting from the deferred consent model and the retrospective discovery of their child's participation in a trial where they may have received a novel therapy. However, experience from our previous trial (ECLIPSE), suggests this is not a major issue particularly where treatment has clearly been successful and the seizure terminated. In ECLIPSE, one of 286 children enrolled died due to complications of convulsive status epilepticus. We have had PPI help in preparing specific material informing the family of a child who has died about the trial.

Where is the study run from?
Liverpool Clinical Trials Centre (UK)

When is the study starting and how long is it expected to run for?
October 2021 to September 2025

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK)

Who is the main contact?
CRESCENT Trial Team
crescent-trial@liverpool.ac.uk

Study website

Contact information

Dr Rob Forsyth
Scientific

Department of Paediatric Neurology
Great North Children’s Hospital
Level 3, Clinical Resource Building 2
Royal Victoria Infirmary
Newcastle upon Tyne
NE1 4LP
United Kingdom

ORCID ID	0000-0002-5657-4180
Email	crescent-trial@liverpool.ac.uk

Dr Rob Forsyth
Principal Investigator

Department of Paediatric Neurology
Great North Children’s Hospital
Level 3, Clinical Resource Building 2
Royal Victoria Infirmary
Newcastle upon Tyne
NE1 4LP
United Kingdom

Email	crescent-trial@liverpool.ac.uk

Dr CRESCENT Trial Team
Public

Liverpool Clinical Trials Centre
Institute of Child Health
Alder Hey Children’s NHS Foundation Trust
Liverpool
L12 2AP
United Kingdom

Email	crescent-trial@liverpool.ac.uk

Study information

Eligibility

Locations

Countries of recruitment

• England
• United Kingdom

Study participating centres

Sponsor information

Funders

Funder type

Government

Results and Publications

Study outputs

Editorial Notes

15/08/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2024 to 31/08/2025.
2. The overall end date was changed from 30/09/2024 to 30/09/2025.
3. The intention to publish date was changed from 31/12/2024 to 31/03/2026.
4. The plain English summary was updated to reflect these changes.
5. The study participating centres Barts Health NHS Trust, University Hospitals of Leicester NHS Trust, University Hospitals of Derby and Burton NHS Foundation Trust, The Royal Wolverhampton NHS Trust were added.
30/05/2024: Publication reference added.
10/05/2024: The recruitment end date was changed from 31/05/2024 to 31/08/2024.
29/04/2024: The following changes were made to the study record:
1. The overall study start date was changed from 04/05/2022 to 01/10/2021.
2. The intention to publish date was changed from 30/09/2025 to 31/12/2024.
05/10/2022: The following changes have been made and the plain English summary updated accordingly:
1. The ethics approval has been added.
2. The recruitment start date has been changed from 01/09/2022 to 01/11/2022.
3. Great North Children's Hospital has been removed from the trial participating centres.
4. The Royal Victoria Infirmary and Associated Hospitals NHS Trust, South Tyneside and Sunderland NHS Foundation Trust, Birmingham Women's and Children's NHS Foundation Trust, Alder Hey Children's Hospital, Royal Alexandra Children's Hospital, Nottingham University Hospitals NHS Trust - Queen's Medical Centre Campus and Leeds General Infirmary have been added to the trial participating centres.
04/08/2022: Internal review.
21/07/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 21/07/2022
09/05/2022: Trial's existence confirmed by NHS HRA.