Title: Seizure control via pH manipulation: a phase II trial of inhaled carbogen as adjunctive treatment of paediatric convulsive status epilepticus
Funder: Medical Research Council

Abstract: 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. Hospital Emergency Departments have well-practiced procedures for this situation in children: they try basic drugs first, but if the seizure hasn’t stopped within a set time they move on to other medicines, and sometimes even admit the child to intensive care units under a full anaesthetic._x000D_ _x000D_ We need better ways to stop long seizures sooner._x000D_ _x000D_ One of the things we think can make seizures more likely to start or stop is the chemistry of a child’s brain, particularly the acid levels. We think being slightly less acidic can make seizures more likely and being a bit more acidic can help stop seizures. 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 and discard carbon dioxide (a “waste” gas) into the air we breathe out. In hospital, children with ongoing seizures are normally given 100% oxygen to breathe while they’re getting other drugs. Carbon dioxide is very slightly acidic: if you put a small amount into oxygen it makes the body (and brain) slightly acidic and may help stop seizures. 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 we normally breathe out._x000D_ _x000D_ This project proposes a clinical trial for children arriving in Emergency Departments still in a seizure. Half the children would receive standard drug treatment whilst breathing 100% oxygen (which is what happens now) and the other half would receive the same standard medical treatment whilst breathing carbogen (95% oxygen and 5% carbon dioxide). This would be a randomised, blinded trial: neither the doctors nor the families would know which gas their child is breathing. We would expect breathing carbogen to make children’s brains very slightly and safely acidic, which might improve how well standard drug treatments stop seizures. We would therefore measure whether seizures stopped sooner in the children who received carbogen, and whether they needed second-stage treatments or admission to intensive care units less often._x000D_ _x000D_ Increasingly we supply the basic drugs to parents and teachers of children known to have epilepsy to use at home or school, aiming to stop the seizure as soon as possible. Unfortunately, these medicines cause drowsiness and can affect breathing, which can be dangerous outside hospital. If carbogen proved to be safe and effective in a hospital setting it may also have a role in homes and schools because it won’t affect people’s breathing and would be easy for parents and teachers to learn to give._x000D_ _x000D_ One important issue is that because this is a trial of treatments for a medical emergency there isn’t time to give information and ask families to think about whether they want to be part of the study. They would have to be included and treated in the study and then be told afterwards and asked if they agreed that we could use the information about their child’s experience. This is known as “deferred consent”. We have recently successfully completed a trial of another treatment of ongoing seizures that had the same issue. We found families understood and accepted why things had to be done this way.

Lay abstract: Background_x000D_ _x000D_ Convulsive status epilepticus (CSE) is the commonest neurological emergency in children affecting 20 per 100,000 children per year and is a frequent event in Paediatric Emergency Departments (EDs). Morbidity relates to aetiology and seizure duration, and despite improved pre-hospital care, mortality remains at 3%. Conventional first line treatments (parenteral benzodiazepines) become less effective with longer seizure duration. Benzodiazepines also cause respiratory depression, limiting their pre-hospital use and contributing significantly to morbidity (e.g. need for high dependency care). Current management protocols stipulate rapid escalation of treatment if seizures have not stopped within defined time limits, culminating in rapid sequence induction (RSI) of general anaesthesia and admission to an intensive care unit (ICU). This process carries significant risk, and such admissions may be prolonged. There remains an urgent and unmet need for effective, non-sedating, adjunctive emergency treatments for paediatric CSE._x000D_ _x000D_ Research question_x000D_ _x000D_ Extensive pre-clinical and pilot data suggest that mild acidosis promotes seizure termination. Mild physiological acidosis can be achieved by replacing the oxygen typically administered by face mask during management of CSE with carbogen, a standard medical gas mixture of 5%CO2: 95%O2, which still provides oxygen in large excess. We hypothesise that higher response rates to first line standard medical treatment of CSE will be seen with adjunctive carbogen therapy. Prolonged carbogen inhalations are used in some radiotherapy protocols and have been shown to be safe and well tolerated._x000D_ _x000D_ Aims and objectives _x000D_ _x000D_ The primary aim is to address whether replacing inhaled 100% O2 with 5%CO2: 95%O2 (carbogen) for the first 10 minutes of treatment for children in CSE in EDs increases the efficacy of the concurrent anticonvulsant therapy, reducing total seizure duration and rates of progression to second line treatment and RSI._x000D_ Objectives are to establish (i) efficacy of carbogen in enhancing response rates of conventional first-line treatments of CSE and (ii) its safety in this context. _x000D_ _x000D_ Methods_x000D_ _x000D_ Double-blind, randomised controlled trial (RCT) using deferred consent, delivering either oxygen or carbogen for the first 10 minutes of ED care alongside standard pharmacological management (after this time, 100% oxygen may be delivered at physician discretion)._x000D_ _x000D_ Timelines for delivery _x000D_ _x000D_ 24 month RCT, with a go/no-go milestone at the 12 month midway timepoint to confirm adequate recruitment, consent and data completion rates. Preceded by a six month trial opening phase and followed by a final six months close-down_x000D_ _x000D_ Should the RCT confirm efficacy and safety this would be an easily implemented and cost-effective modification to current ED management protocols for childhood CSE. Given the clear potential for use by lay personnel (e.g. families and teachers), further RCTs in pre-hospital settings (e.g. paramedic crews) could be considered.

Research activity codes: 6.7 PHYSICAL
Health categories: NEUROLOGICAL