A trial of non-invasive ventilation and in children with cerebral malaria (NOVICE-M)

What is the problem/background?

Children with cerebral malaria continue to have very poor outcomes. The SMAART: Severe Malaria in African children: A Research and Trials consortium have identified one key innovation which could improve this. We will explore the potential benefits of a special type of ventilation that applies suction or negative pressure to the chest (meaning keeping children breathing by pushing air in and out of their lungs) in combination with anticonvulsants given before children have had any fits, as a way to prevent them stopping breathing completely and/or preventing or reducing the amount of pressure that builds up in their brains which can lead to death, or brain damage and disability over the long-term.

A device called biphasic Cuirass Ventilation (BCV) is a portable device that helps push air in and out of children’s lungs, without needing to put a tube down their throats. It does not need doctors to set it up, and can be used across a wide weight and age range. BCV is also used outside of hospitals by non-specialists (called paramedics) to help children breath. This technology innovation could be readily transferred to Africa to hospitals that have no access to the large and expensive machines that are used in high income countries to breathe for children (called mechanical ventilation). So BCV could be an alternative solution for ventilation in Africa, if studies showed that it could be safely and effectively implemented. BCV applies both negative and positive pressure to the chest, covering both inspiration (breathing in) and expiration (breathing out) phases of breathing, which is more appropriate for periods of when the breathing is too slow or stops for a period of time rather than other types of respiratory support. For example, a different kind of machine (called ‘CPAP’) is used in young infants with breathing difficulties. However, this only provides positive pressure and needs the child to be spontaneously breathing to benefit from it. During this trial we will be checking to see if the breathing is fully supported during the times it is too slow or stops. This may lead to a buildup of one of the gases that is breathed out called carbon dioxide. We will be monitoring this. If this does happen we will use another machine called AIRVO2 that produces High Flow air/oxygen mix to help reduce this build up of carbon dioxide. We will also be using a newer anticonvulsant drug to prevent seizures; this is called levetiracetam which has been used in Malawian children and shown to improve outcomes (reduces seizures and adverse events). This will be given directly into the stomach via a nasogastric tube (tubes down the nose into the stomach). The dose we will test first the standard dose that was safely used in the Malawian trial.

Given its potential to be transformative in improving current outcomes from cerebral malaria, a large group of specialist doctors in severe malaria research, together with world leaders in negative pressure ventilation research (Professor Brian Kavanagh, Sick Kids, Toronto and Professor John Fraser Critical Care Group, Brisbane) suggested that BCV should be tested. They have all helped to design this clinical trial, which will be conducted on the high dependency ward in Kilifi, Kenya.

We will explore the potential benefits of negative pressure ventilation (NPV) in combination with prophylactic anticonvulsants to ameliorate the adverse outcomes secondary to cerebral malaria (CM). The major pathophysiology in cerebral malaria is an increase in the overall cerebral volume and vasogenic raised intracranial pressure (distinct from raised intracranial pressure associated with meningitis) as a result of parasite sequestration, venous congestion, or ischaemia due to seizures. Prophylactic anticonvulsant medication could avert ‘spikes’ of intracranial pressure during repeated seizure events; yet with current treatments (diazepam, and phenobarbitone as second-line) these come at a risk of hypoventilation and respiratory arrest, as demonstrated in the phenobarbitone trial. In high-income countries, management incorporates mechanical ventilation; but this is not available in the majority of resource-limited hospitals in Africa. Alternatives to intubation and mechanical ventilation include non-invasive ventilation (NIV), which has been proven to work in a wide range of patients including those with central hypoventilation syndrome. We propose to prevent the major pathological complications of CM and major mode of death, respiratory arrest, by preventing or reducing intracranial hypertension by targeting the cerebral vasodilation (through the use of a prophylactic anticonvulsant, levetiracetam) in combination with NIV as a promising strategy to avert deaths and neurological sequelae from CM. Biphasic Cuirass Ventilation (BCV) is a NIV system that is portable, requires no intubation, does not require specialist medical personnel, and can be used across a wide weight and age range (http://www.hayekmedical.com/about-bcv/). BCV could be transferred to Africa if studies showed that it could be safely and effectively implemented. We will conduct a phase I trial to generate feasibility, safety and preliminary data on seizure control of BCV as non-invasive ventilatory support in cerebral malaria with and without prophylactic anticonvulsant (levetiracetam).