The CRASH Trials: Studies on Lowering Risk of Death due to Brain Injury
Wed, April 21, 2021

The CRASH Trials: Studies on Lowering Risk of Death due to Brain Injury

Researchers analyzed the effects of infusing corticosteroids and TXA to patients with TBI / Photo Credit: 123RF


There are over 60 million new cases of traumatic brain injury (TBI) made globally each year mainly due to car accidents and falls. A common implication of TBI is intracranial bleeding—bleeding inside the skull—that increases the risk of death, especially if the bleeding persists.

For years, researchers have been looking for the most efficient way to reduce the risk of death by lowering in-skull building. Since 2001, scientists have carried out the Clinical Randomisation of an Antifibrinolytic in Significant Head Injury, or CRASH, trials to determine the effectivity of corticosteroids (steroid hormones) and tranexamic acid (TXA) in treating intracranial bleeding.


Design and organization

CRASH is a randomized, placebo-controlled trial that analyzed the effects of infusing corticosteroids (one trial) and TXA (two trials) in patients with brain injury and some impairment of consciousness for 48 hours.

According to the trial protocol, patients with impaired consciousness "who are judged to be 16 years or older are eligible if the responsible doctor is, for any reason, substantially uncertain whether or not to use corticosteroids."

They carried out the trial in thousands of brain injuries from numerous countries across three trials: 10,008 adults patients from 49 countries in the first trial, 20,211 from 40 countries in the second trial, and over 9,000 patients across 29 countries in the third trial.

The drugs, along with a placebo, were given at random to the eligible patients.



The first trial

The first CRASH trial looked into head injury in 10,008 adults patients from 49 countries using corticosteroids and placebo. Patients were given a random treatment pack number that identified the CRASH treatment packs stored in the hospital's emergency department and were monitored for six months to observe the effects.

After six months, the researchers concluded that administering corticosteroids did not reduce the risk of death due to brain injury. Instead, they recommended that the drug not be given to patients with TBI.

The first trial showed that administering corticosteroids raised the risk of death by 25.7 percent compared to placebo use with a 22.3 percent increased risk, as per the The Bottom Line. Using the said drug also increased mortality or severe disability by 38.1 percent.

The Bottom Line is a UK-based website that summarizes landmark papers and studies that shape the management of critically ill patients.

"Corticosteroids should not be given to patients with head injuries unless other specific indications exist that outweigh the increased risk of death demonstrated by this trial," the UK website said, based on the first trial's results.


Tranexamic acid and head injuries

The second trial was conducted nine years after the first CRASH test. In this study, the researchers assessed the effects of TXA on 20,211 adult head trauma patients from 40 nations. TXA is a medication commonly used to treat or prevent excessive blood loss from injuries—such as surgery, tooth removal, nosebleeds, and heavy menstruation—as it slows the breakdown of blood clots.

CRASH-2 trial followed the same procedure as CRASH-1 00 randomly administering TXA to a portion of the patients and a placebo to the other portion.

Final results show that TXA safely reduces the risk of death in bleeding trauma patients—which prompted researchers to recommend administering TXA to such patients as early as possible, according to the Lancet medical journal.

There was a 4.9 percent lower risk of death among the patients given TXA compared to the placebo group (5.7 percent). Results also show that all-cause mortality decreased for those who were given the drug (14.5 percent) against those who took the placebo (16 percent).



A landmark study

The third and most recent CRASH trial has been dubbed as a "landmark study" for demonstrating reduced mortality after a traumatic brain injury.

Antonio Belli, professor of trauma neurosurgery at the University of Birmingham, told The Independent.

Belli added that aside from saving thousands of lives worldwide, results of the CRASH-3 trial "will no doubt renew the enthusiasm for drug discovery research for this devastating condition."

CRASH-3 trial focused on over 9,000 patients across 29 countries. At random, the patients were treated within three hours of injury and were given either the TXA—which cost about £6.20 per person—or placebo at random via intravenous therapy (IV).

Those who obtained mild or moderate traumatic brain injury and were given TXA demonstrated a lower risk of death.

The Guardian reports that the risk of death reduced to 22 percent for patients who received the drug compared to those who were given a placebo. Merely 5.8 percent of the 2,846 patients given TXA died compared with 7.5 percent of the 2,769 patients given placebo.


Results showed that infusing TXA to patients lowers the risk of TBI death cases / Photo Credit: 123RF


Very good news

Reducing the bleeding could help save the patients' lives since they bleed more slowly, according to Ian Roberts, a co-leader of the study. Although he warned that stopping the bleeding also "stops them developing a big bruise inside the head which can squash the brain and kill you."

Still, the CRASH trials have come a long way after decades of research and failed attempts.

The recent study not only supports the CRASH-2 trial, but it also demonstrates that the drug doesn't increase the possibility of disability or other negative events like stroke.

"Bearing in mind that 90 percent of head injuries are mild and moderate, this is very good news because you have got something that can prevent bleeding into the brain that could kill them, and if they don’t die they are in good shape," Roberts concluded.