Q&A: ‘Kitchen sink’ approach continues to guide research for TBI treatment

Key takeaways:

• Scientific advancements for traumatic brain injury have lagged compared with other areas of medicine.
• The Brain Trauma Foundation and Military Traumatic Brain Injury Initiative are developing new guidelines.

March is Traumatic Brain Injury Awareness Month, a condition that has led to permanent disability in more than 5 million individuals in the United States.

Healio spoke with Gregory Hawryluk, MD, PhD, medical director of the Brain Trauma Foundation (BTF) and a neurosurgeon with the Cleveland Clinic, about the state of science behind potential treatments for this complex neurological puzzle.

Healio: Is there a lack of effective treatments for traumatic brain injury (TBI)?

Hawryluk: The Brain Trauma Foundation’s guidelines have been repeatedly shown to markedly reduce mortality from severe traumatic brain injury — often by more than 50%. This is true of our flagship adult coma guidelines, as well as our prehospital guidelines. If scientists invented a pill that was this effective, they would likely win a Nobel prize.

Basic science advancement for TBI has certainly lagged behind other areas of medicine. Molecular mechanisms of brain injury are highly complex and redundant and therapeutics targeting a single pathway may be doomed to fail. Some experimental therapeutics may not have crossed the blood brain barrier sufficiently.

Heterogeneity of human brain injury is a marked impediment to research as it can obscure treatment effects. Some of the most important studies in head injury seem to have overcome this heterogeneity with sample sizes of over 10,000 patients, but this is not a feasible number to enroll for most clinical trials.

I think it is also important to consider that some fundamental gaps in knowledge may be impeding our ability to progress. The importance of cerebrovascular autoregulatory processes have only recently received widespread recognition. This is a process by which cerebral vessels can dilate or constrict and alter the cerebral blood volume to compensate for changes in nutrient supply. This change can contribute to alterations in the pressure inside the head which can be harmful.

Scientists also recently rediscovered a phenomenon referred to as cortical spreading depressions/depolarizations which have the potential to explain many clinical observations that previously seemed hard to explain. As these can be treated with N-methyl D-aspartate receptor antagonists, we are now racing to better understand the role of monitoring and treating these phenomena.

Healio: What treatments for the condition are currently in the pipeline?

Hawryluk: The kitchen sink approach still applies, where people are trying every conceivable approach, albeit with less fervor than in the 1980s because of the failure of so many trials in this field.

Given the high risk of trial failure, fewer trials are being initiated and funded. Research broadly seeks to address neuroprotection, neural regeneration and compensatory mechanisms.

Neuroprotection builds upon the recognition of delayed cell death for a prolonged period after the initial injury and drugs continue to be developed with the aim of interrupting this delayed cell loss. Neural regeneration aims to replace lost cells or to stimulate their regrowth to an extent greater than what is seen with normal healing. Compensatory mechanisms aim to lessen functional deficits by bypassing a neural injury as with neural implants or neural modulation.

We also believe that much remains to be learned and optimized about clinical care — in particular, optimizing the physiology that follows brain injury to prevent further injury and optimize healing. The BTF is currently conducting a trial of lumbar cerebrospinal fluid drainage based on a hypothesis that this can be used to either safely prevent or treat intracranial pressure elevation.

Healio: Can you briefly discuss the genesis of the collaboration between the BTF and Military Traumatic Brain Injury Initiative and its main goals?

Hawryluk: This symbiotic relationship grew organically. Dr. Randy Bell — at the time chief of neurosurgery at Walter Reed Military Medical Center — expressed interest in working with us to develop new guidelines for the management of penetrating brain injury.

We agreed that new guidelines were badly needed and began a 5-year process to procure funding and conduct an extensive project involving over 40 experts from around the world to provide a combination of evidence and consensus-based recommendations for best care. The success of this project inspired a dramatic expansion of the collaboration.

The Military Traumatic Brain Injury Initiative has provided us with the resources to be extremely productive.

We’re developing guidelines for the following: combat and austere care environments; assessing soldiers and athletes’ readiness to return to combat or sport; and an updated fifth edition of our flagship adult coma guidelines.

At the heart of this collaboration is a recognition that the military possesses unique experience with the most extreme forms of TBI which very few civilian neurosurgeons accrue. There has long been a tradition of “military-civilian translation” in neurosurgery, whereby civilian care learns lessons vicariously from our colleagues in uniform whose unique experience and wisdom is passed on to the rest of neurosurgery. It is a great privilege to work with them and to learn from them with the goal of improving head injury outcomes.

Healio: What health disparities do patients with TBI face and what is the BTF doing to address them?

Hawryluk: There is a need to provide the highest quality care possible to head injured patients when a neurosurgeon, CT scanner or intensive care unit are not available. This is a scenario of relevance to injured soldiers and to many patients treated around the world. The BTF’s goal is to improve outcomes from head injury for as many patients as possible and we have recognized that guidelines which can only be enacted in optimally resources care environments are not enough.

Healio: The BTF created certain standard of care guidelines to reduce deaths from TBI. What are some key takeaways from these guidelines?

Hawryluk: We have published numerous guidelines on important TBI subtopics.

The basic rationale for our work is that the identification of best practices and the promotion of these practices must invariably lead to better patient outcomes. Indeed, a marked improvement in outcomes is what we have seen repeatedly when our guidelines are implemented.

While we have published hundreds of recommendations on diverse topics, some common themes emerge, most importantly the recognition that strong efforts to resuscitate patients are key to optimizing outcome. Avoiding low blood pressure, low oxygen levels, high brain pressures, seizures etc., are believed to be crucial. We’ve learned it is important to feed patients.

Some important recommendations have determined that practices based on physician intuition that used to be common were actually harmful. Key examples of this were the administration of steroids and the practice of routine hyperventilation. It has become clear that we need evidence to inform all aspects of brain injury care to determine if the things that we think are beneficial, truly are.

For more information:

The work of Gregory Hawryluk, MD, PhD, and others within the Brain Trauma Foundation can be found at: https://braintrauma.org/.