New discovery: Fluid build-up from brain injury can be halted

 
Victims of road-traffic accidents and other causes of traumatic brain injury (TBI) typically suffer cerebral oedema; fluid build-up that damages even more brain tissue and can be life-threatening. A new discovery could help doctors reduce the volume of fluid.

When an ambulance brings a crash victim with a head injury into hospital the doctors check for visible and invisible injuries and initiate treatment. They measure the patient’s vital signs, and if the blood pressure, for example, is too low, they administer a shot of the signalling substance noradrenaline.

But noradrenaline is the last thing the patient needs. The accident, followed by the many diagnostic tests, will already have triggered natural noradrenaline release in the body and brain, and at high levels, this substance halts drainage of fluid from the head, which causes cerebral oedema, a life-threatening fluid build-up in the brain.

This was demonstrated by Professor Maiken Nedergaard together with a team of fellow-Danish and American researchers in a recent study funded by the Lundbeck Foundation and just published in Nature.

‘Our data show that injecting patients with noradrenaline is harmful. Those shots must be avoided because then the patients will suffer less oedema in the acute phase,’ says Nedergaard.

The professor splits her time between her laboratories at the Center for Translational Neuromedicine, University of Copenhagen and a counterpart lab at Rochester University, New York. If her name rings bells that may be because Nedergaard was the one who made the crucial discovery that the brain has a cleansing system, the glymphatic system, which removes waste substances from the brain by rinsing it with fluid at night while we’re asleep. 

Her discovery has been of great significance for sleep research and research in brain disorders.

In the new study on cerebral oedema, Professor Nedergaard investigated why and how fluid builds up in the brain within the first two hours of a head injury, and whether it is possible to limit or prevent the oedema.

Oedema is the worst risk factor

Between 55 and 74 million people worldwide sustain TBI from assault, road-traffic accidents or a fall, for example. A common complication of TBI is acute cerebral oedema, which increases the risk of death tenfold and may cause disability in survivors.

The fluid exerts pressure on the blood vessels and compromises the blood circulation so that more brain tissue dies. The build-up of dead brain cells causes inflammation, which in turn worsens the oedema.

‘Oedema is probably the worst risk factor after acute brain injury.  That was one of the reasons why we initiated the study,’ Nedergaard explains.

Another reason was her interest in investigating the effect of noradrenaline on the glymphatic system.

‘Noradrenaline is the most potent control mechanism in the glymphatic system. The minute we wake up in the morning, our glymphatic system switches off, and that’s because of noradrenaline,’ she explains.

 ‘But we also know that the natural “fight or flight” response makes our noradrenaline level rise if we’re injured. Which is why we wanted to investigate the implications of the increase in the acute phase of TBI.’

The researchers studied the mechanisms in mice that were lightly anaesthetised before being exposed to a “hit-and-run” head injury.

They discovered that excess noradrenaline suppresses fluid downflow from the brain’s glymphatic system into the lymphatic vessels between the jaw and neck.

The constriction of these vessels prevents the flaps inside them from opening to allow the fluid to pass through. Within just 30 minutes of the injury, fluid begins to build up in the brain.

But noradrenaline signalling can be dampened by a number of substances called receptor antagonists, which block the receptors on the cells noradrenaline otherwise binds to. And the researchers identified a “cocktail” of three different types that cover all the receptors.

Brain may be self-cleansing

With treatment 24 hours after the injury, fluid regulation was restored to near-normal, allowing waste substances and dead cells from the injury site to be cleared from the brain.

The mice that received the treatment performed better long term in both physical and cognitive tests than untreated mice, which still showed reduced glymphatic flow six months after injury.  

Professor Nedergaard hopes that neurosurgeons will follow up the study with clinical trials, and that her discovery will lead to changes in hospital procedure. Aside from holding back on the noradrenaline shots and drugs to prevent noradrenaline receptor binding, she hopes that doctors will also ease up on their acute checks of the patients’ neurological status such as shining a bright light in their eyes.

‘Several studies show that the more diagnostic tests patients are subjected to immediately post-injury, the worse their complications will be. And it’s all to do with noradrenaline. Shining a light into the eyes of patients trying to rest, or who are unconscious, is likely to increase the amount of noradrenaline. In many cases, patients could be left in peace in a dark room, and only have their blood pressure and respiratory rate measured, to give the glymphatic system a chance to cleanse the brain after the injury.’

Meanwhile, Professor Nedergaard and her research team will be continuing their investigation of the mechanisms behind fluid build-up in the brain. Now, however, their research will focus on the oedemas that typically arise three to four days post-injury.

‘We know that there is a correlation between the severity of the two oedemas, but we don’t know what causes the fluid build-up several days after the injury, so this is an obvious research topic.’

How fluid drains into the lymphatic vessels

The video shows how the treatment that inhibits the receptors has boosted fluid flow in a murine (mouse) lymphatic system.  The damaged cells (black particles) following head injury are washed out via the lymphatic vessels (green oblongs). The red dots are fluorescent microspheres used by the researchers for measuring the fluid flow rate; a technique developed by Nedergaard in collaboration with an American fluid dynamics engineer.

For a more comprehensive understanding of this research, you can access the detailed study here (behind a paywall)