A drug previously known for its anti-epileptic properties is now being used to extend survival time immediately following major trauma and blood loss.
After a traumatic injury with major blood loss, survival is highly dependent on the time it takes for the patient to receive a blood transfusion. The longer the time elapsed, the greater the risk of death. Researchers at Harvard University have tested a new drug called valproic acid (VPA) on animals suffering major blood loss and found that it leads to increased survival rates. Hasam Alam, primary investigator on the research team, recently told New Scientist magazine: “You can’t carry a blood bank into the battlefield. What we’re looking for is a pill or a shot that would keep a person alive for long enough to get them to a hospital.”
While current resuscitation strategies include intravenous drug administration, recent studies show that this technique can actually exacerbate cellular injury. In an ideal world, the wounded patient would simply receive a blood transfusion, but a number of challenges—blood type and matching requirements, the perishability of blood units, and the need to refrigerate blood products—make this approach impractable. Another solution is necessary.
Shock following major blood loss results in cellular injury, which can then lead to organ failure, and ultimately death. When the body goes into shock, it inhibits the expression of certain proteins. VPA is hypothesized to act on this pathway by preventing protein inhibition, thus decreasing the cellular damage associated with shock. This process is thought to be accomplished through a fast-acting, intricate signal cascade resulting in altered gene transcription.
Alam and his research team first conducted experimental studies using VPA on rats. In this rodent model, VPA improved survival in lethal hemorrhagic shock. Alam’s newest study has taken it one step further to a more clinically relevant animal model using swine. A forewarning for the weak-stomached reader: vascular trauma studies, like the one described below, are notorious for their gruesome nature.
Alam’s pigs were anaesthetised, followed by a 60 per cent total blood volume drainage, and subjected to a femoral fracture, among other injuries, before receiving a saline transfusion. The pigs were then either given a fresh blood transfusion, intravenous VPA, or left untreated. The animals were then monitored over four hours with survival being the endpoint of interest.
Researchers found that blood transfusion resulted in a 100 per cent survival rate, while VPA and the untreated group had survival rates of 86 per cent and 25 per cent, respectively. It should be noted that only one pig that received the VPA treatment died, due to a complication in VPA infusion before the monitoring period commenced. Dr. Sandro Rizoli, director of the trauma, emergency, and critical care program at Sunnybrook Hospital and associate professor at U of T, thought this was an “excellent” study. However, he also extends caution about “extrapolating the results of this study to humans [from] an animal model, including only a small numbers of animals [with only] six to eight per treatment group.”
Dr. Najma Ahmed, professor of surgery at U of T with a clinical focus on trauma and critical care, believes that such a drug may have potential benefits in decreasing the chance of death following blood loss, but that possible side effects should be considered. When VPA is used as an anti-epileptic, “toxicity is rare [but] it has been reported and […] can cause a wide range of central nervous system disturbances, renal failure, and affects almost every organ system in the body.”
The potential benefits of VPA treatment on humans is only in its preliminary test stages. Alam’s team is still unsure about the exact mechanism through which VPA activity fosters survival. Ahmed expressed that a small-scale human study is likely the next logical step, but this requires “closely monitored study subjects, particularly as it relates to long-term consequences.”
