A research group at NUI Maynooth has worked out why anaesthesia can kill some patients before the surgeon gets anywhere near them, writes Dick Ahlstrom
A crafty bit of detective work has unearthed the biochemical trigger for a rare but life-threatening allergic reaction to certain anaesthetics. The work could save lives and also lead to safer drugs.
The research relates to a condition known as malignant hypothermia and is seen in patients in theatre who receive the anaesthetic halothane.
"It is a very rare disorder," says Prof Kay Ohlendieck, who heads NUI Maynooth's biology department.
It only affects those with an inherited susceptibility to the disorder.
"If you are exposed to the anaesthetic halothane, you go into a metabolic crisis."
Within seconds, patients experience muscle rigidity and a sudden increase in body temperature. Calcium enters muscle tissue leading to the dramatic breakdown of the cells. This in turn releases cell contents that poison the system and also discharges large amounts of potassium that can affect the heart and kidneys.
"It is extremely rapid and the temperature rises very quickly," says Ohlendieck. "In the past, people died from this but now they are given an antidote."
Researchers in UCC's department of biochemistry led by Prof James Heffron have done extensive work on malignant hypothermia. He entered a research collaboration with Ohlendieck and PhD student Louise Glover in Maynooth, using Health Research Board funding.
The goal was to identify the biochemical cause of the disorder, the receptor site trigger that reacts to the presence of halothane. The three published their findings last month in the American Journal of Applied Physiology.
"We were looking at two things: we were trying to understand malignant hypothermia and also to find the drug's binding site," says Ohlendieck. "We found it binds to one particular receptor, the ryanodine receptor, and it aggregates there. It releases calcium into the cell and that probably triggers all of these symptoms."
The team in Maynooth received muscle tissue samples from Cork, some of normal muscle and some from patients sensitive to halothane. Ohlendieck and Glover, who has gone on to study muscular dystrophy at Harvard University in Boston, had to separate all the proteins found in these cells.
This was done using an electrophoresis gel system that separates samples on the basis of molecular size. Each protein group then had to be inoculated with halothane and then re-gelled to see which protein or proteins were changed by the drug, seen as a "band shift" in the gel.
This helped identify the single protein receptor to which halothane binds. The researchers also showed that susceptible patients responded strongly to the drug.
"We found that the patient samples are much more sensitive to the drug even at low concentrations," says Ohlendieck. "Somehow the receptor seems to be more susceptible for the binding and then the aggregation.
"Now that we have a site the drug binds to, we want to study where exactly it connects."
The team only has limited information on the nature of the connection between the drug and the receptor, something that will provide important information when it comes to studying alternatives to halothane.
Ohlendieck believes that incidence statistics for the disorder may be misleading.
"The frequency is about one in 15,000 children and one in 50,000 adults, but the real incidence could be one in 1,000," he says. This is because there are many who will never encounter the drug and others who would only receive low-level exposure during treatment.