Oxygenation as Treatment for Brain Injury
Should we treat brain injury patients with oxygenation? It seems an almost silly question. Surely it’s that obvious that we should! Yet when we investigate the utility of pumping large amounts of oxygen into an injured brain, it turns out that the answer is not that simple.
A quick search of the web will show you that there are many facilities offering such oxygenation treatment. The rationale is simple. In a newly injured brain, there is a metabolic crisis and there is insufficient energy. Furthermore, secondary brain injury can arise from lack of oxygen (hypoxia). So, why not hit the patient with lots of oxygen to prevent hypoxia? Seems sensible, right?
Wrong!
Hyperbaric Hype
Before I clarify my objection, I’d like you to understand the broader context in which these issues play out. A typical scenario is that someone suffers a brain injury in a motor vehicle accident. They’ve been lying in ICU in a semicoma for some days and the doctors don’t seem to be doing anything. The lines of communication seem limited. The family are desperate. Then someone searches the internet for “cure for brain injury” and finds the answer—a book entitled The Oxygen Revolution: Hyperbaric Oxygen Therapy: The New Treatment for Post Traumatic Stress Disorder (PTSD), Traumatic Brain Injury, Stroke, Autism and More.
The internet is incredible; in 30 seconds you can find the answer for intractable medical problems that have eluded science for decades. The Oxygen Revolution is so popular that it is now in its third edition. As you can tell from the title, the authers claim that hyperbaric oxygen therapy is the ultimate cure-all. Here is quote from the advertising for the book:
It seems too good to be true, but Dr. Paul G. Harch’s research and clinical practice has shown that this noninvasive and painless treatment can help the tens of millions of Americans who suffer from a brain injury or disease, such as:
Amazon.com
Stroke
Autism and other learning disabilities.
Cerebral palsy and other birth injuries.
Alzheimer’s, Parkinson’s, multiple sclerosis, and other degenerative neurological diseases.
Emergency situations requiring resuscitation, such as cardiac arrest, carbon monoxide poisoning, or near drowning.
It can also improve conditions in which inflammation is the culprit, such as arthritis and asthma; promote healing in infections, burns, and skin grafts, such as diabetic foot wounds; and slow the aging process.
Wonder Elixir
Wow! Not since Dr Poppy’s Wonder Elixir has there been such a miraculous treatment. Using this treatment means that not only can we cure your brain injury and sort out your diabetes, but you’ll hop and skip out of the ICU with a beautiful skin and looking years younger. Pay now and take your place in the queue…
Let’s have a reality check; there are some tantalising, genuine findings that suggest that there are benefits from hyper-oxygenation and which require our attention. For example, animal research shows benefits from hyperbaric treatment in concussion.
Appreciate that oxygen can be delivered under pressure (hyperbaric) or at normal atmospheric pressure (normobaric). Hyperbaric treatment requires a sealed chamber, but normobaric treatment only requires a face mask or tube and an oxygen supply. Hyperbaric treatment is obviously difficult in the ICU and normobaric treatment is therefore what we use in the real world; let’s focus on normobaric treatment and forget about hyperbaric treatment and the quest for eternal youth.
Evidence in the Real World
In a small trial, 68 patients with severe TBI were randomly assigned to receive either 80% or 50% oxygen via mechanical ventilation for the first 6 hours after injury. The hyperoxia (80%) group had a better outcome. Another study showed a significant reduction in risk of dying in patients with hyperoxaemia (excessive oxygen in the blood). Well, the association held in the univariate analysis, at any rate. However, the multivariate analysis showed no association between hyperoxaemia and reduced mortality. So, the link between outcome and high levels of oxygen is complex and mediated by multiple factors. I guess it is hardly suprising that the link is not straightforward! This result sounds a cautionary note.
Easy as We Go
Of course, there are other examples of positive findings in the literature, but this blog is not a review of that topic. Rather, the aim is to sound a word of warning. To avoid harming patients and prevent medicolegal hazards, a careful approach to hyperoxia treatment is necessary. Desperate families may be seduced by the hype associated with claims made for hyperbaric oxygen treatment. They may give consent to procedures that may backfire. The critical point is that the safety and efficacy of hyperoxia has not been properly established and it should be regarded as an experimental treatment.
Too much oxygen in blood (hyperoxaemia) or tissue (hyperoxia) is abnormal. It never occurs under normal physiological conditions. On the other hand, hypoxaemia and hypoxia occur in the real world, for example, in pulmonary disease or at altitude. Providing supplementary oxygen for hypoxaemic patients may help to normalise cellular metabolism and limit brain dysfunction. However, in patients who are not hypoxaemic, supplemental oxygen will increase oxygen concentrations into hyperoxaemic ranges.
What Goes Wrong with Oxygenation
Importantly, our physiology does not have a mechanism for dealing with hyperoxia, whereas we are equipped to deal with hypoxia via a process called autoregulation. Hyperoxia results in the production of reactive oxygen species (ROS), which trigger apoptosis (programmed cell death) and which causes brain damage. (That’s an oversimplification, of course.) Interestingly, the effects of too much oxygen on the brain are similar to the effects of too little, and these patients have similar neuropsychological profiles.
One study of 3,420 TBI patients found poor outcome in those with hypoxaemia and those with hyperoxaemia; too much or too little oxygen is bad. Another project allocated patients to supplemental oxygen or just room air, but was discontinued when it was found that far more patients in the oxygen supplementation group were dying.
A recent study used diffusion tensor imaging (DTI) to measure the effect of normobaric hyperoxia on brain injury. They used before and after treatment DTI brain scans to investigate axonal injury. Their focus was on the integrity of nerve fibre tracts some way away from contusions. They found that treatment showed no benefit. In fact, some regions showed reduced fractional anisotropy (fluid flow), indicating worsening of injury. Using brain oxygen sensors that are inserted directly into the brain, other researchers found that hyperoxia was only beneficial in patients with low oxygen on admission. That is an important point. At the very least, we should only use this treatment in suitable candidates.
Can Oxygenation Cause Harm?
Then, there is a study that threatens to completely upset the apple cart by suggesting that supplementary oxygen may be harmful, even at low concentrations of the kind used in routine clinical practice. These researchers (Quintard et al, 2015) examined the effect of oxygen on glutamate concentrations in the brains of patients with severe brain injuries. Glutamate is an excitatory neurotransmitter and while it is a normal component of brain neurochemistry, when concentrations are too high, glutamate triggers secondary excitotoxic brain injury.
Quintard and his team related the concentration of supplementary (facemask or tube) oxygen (fraction of inspired oxygen; FiO2) to glutamate levels in the brain. They measured glutamate with a microdialysis sensor in the brain, so the measure couldn’t be more direct. The researchers also monitored brain tissue oxygen using sensors within the brain.
They showed that levels of glutamate increased as FiO2 increased; the greater the amount of oxygen that was given, the higher the glutamate levels, as shown in the figure. This applied even with low levels of inspired oxygen, FiO2 = 40%. They found that hyperoxia (PaO2 > 150 mmHg) was strongly associated with increased release of glutamate and that this effect was independent of brain tissue oxygenation.
This suggests that supplementary oxygen may be inducing glutamate expression and triggering a cascade that leads to secondary excitotoxic brain injury. Whoa! That’s scary, especially since providing a patient with supplementary oxygen is common clinical practice. Here we are not necessarily even talking about deliberate hyperoxia, as much as simple supplementary oxygenation. It is appropriate to keep in mind that any supplementation of oxygen is “supra-normal,” i.e. exceeds atmospheric levels.
Implications for Oxygenation
There may be benefits for some TBI patients, especially those who are hypoxic at the time of admission, but hyperoxia is not treatment that will benefit all patients. Once the patient is no longer hypoxic, we need to be very careful about further oxygen supplementation. One wonders if these findings do not explain the association between cognitive impairment and prolonged ventilation in patients who have not suffered brain injury.
The lesson is simple: hyperoxia is not a cure-all and careful patient selection is required to avoid harm. Failure to do so would be negligent. Treatment decisions should not be influenced by internet hype, grandiose claims, or pleading family members, but on rational science, and right now the evidence doesn’t look too good.
