Propofol Could Cause Fatal Reaction in Refractory Status Epilepticus

From CHEST 2008: American College of Chest Physicians 74th Annual Scientific Assembly

October 29, 2008 (Philadelphia, Pennsylvania) — Mayo Clinic researchers warn that the sedative propofol can cause propofol infusion syndrome, an irreversible chain of events associated with significant morbidity and mortality, in the treatment of refractory status epilepticus.

“Treatment guidelines specify the first 2 drugs to be used to control status epilepticus… are lorazepam and phenytoin, but it has been unclear what the third line of treatment should be,” said Vivek Iyer, MD, a first-year fellow in the Department of Pulmonary Critical Care Medicine at the Mayo Clinic in Rochester, Minnesota.

Dr. Iyer presented findings of a series of patients with refractory status epilepticus who developed propofol infusion syndrome to attendees of CHEST 2008: American College of Chest Physicians 74th Annual Scientific Assembly, which is being held here this week.

“Propofol is a very commonly used sedative, and we used it to control refractory seizures, until we began to notice that some patients were experiencing adverse events,” he told Medscape Pulmonary Medicine during an interview after his presentation.

Propofol infusion syndrome is defined as the unexplained presence of 1 or more of the following symptoms: bradycardia, metabolic acidosis, renal failure, rhabdomyolysis, cardiac failure, and cardiopulmonary arrest. “Once the symptoms have started, it is usually quite aggressive in its course and is usually irreversible,” Dr. Iyer noted.

The Mayo Clinic researcher presented a series of 39 patients with refractory status epilepticus who developed propofol infusion syndrome at the Mayo Clinic between 1997 and 2007. This group was compared with a similar group who received third-line treatment with phenobarbitol or versed.

Propofol was infused for a median of 63 hours (range, 2 – 391 hours) with a median cumulative dosage of 12,750 mg (range, 336 – 57,545 mg). The median peak infusion rate was 67 µg/kg/minute (range, 19 – 200 µg/kg/minute). “This was an average of 150 – 300 mg an hour,” Dr. Iyer noted.

Bradycardia occurred in 7 patients receiving propofol but in only 1 patient who received phenobarbitol.

There were 3 sudden unexplained cardiorespiratory arrests in the propofol group (10%), of which 2 were fatal. These patients had no prior cardiopulmonary disease. There were no cases of cardiopulmonary arrest in patients who did not receive propofol.

Propofol infusion syndrome “…is a relatively rare occurrence, but there is very little you can do once these symptoms start,” Dr. Iyer emphasized. “It has a very aggressive course … Of the 3 patients who went into cardiopulmonary arrest that we resuscitated, only 1 survived.”

“Since propofol is so commonly used, we thought it would be safe. It has a half-life of only about 40 minutes. But there is something else apart from its intended effects going on here, maybe an interference with the mitochondrial energy production, leading to heart dysfunction,” Dr. Iyer speculated.

“You need to give it in a dose that is an order of magnitude greater than usual for refractory status epilepticus. Instead of giving it as a bolus of 150 – 300 mg, we were giving it at 150 mg an hour.” The median length of infusion time was 63 hours, he pointed out.

“Propofol is one of the most commonly used sedatives. If you’ve had a colonoscopy, chances are you’ve had propofol,” panel moderator Mark J. Rosen, MD, FCCP, chief of pulmonary, critical care, and sleep medicine at North Shore Health System and professor of medicine at Albert Einstein College of Medicine in New Hyde Park, New York, told meeting attendees. “Propofol infusion syndrome is a very rare problem for a very commonly used drug.”

“Since we started looking into this, we have completely shifted away from using propofol,” Dr. Iyer reported. “We use midazolam or pentazolam, instead, as third-line treatment of refractory status epilepticus. There are other options. We don’t need to use this drug.”

Dr. Iyer and Dr. Rosen have disclosed no relevant financial relationships.

CHEST 2008: American College of Chest Physicians 74th Annual Scientific Assembly: Abstract AP2328. Presented October 28, 2008.

Pearls for Practice

• Current treatment guidelines specify the first 2 drugs to be used for refractory status epilepticus are lorazepam and phenytoin, but it is unclear what should be used as the third-line of treatment. Propofol, however, has been used as third-line treatment but has caused adverse effects.
• Propofol given at an infusion rate of 67 µg/kg/minute for treatment of refractory status epilepticus caused propofol infusion syndrome. The syndrome is rare and is defined as the unexplained presence of 1 or more of the following symptoms: bradycardia, metabolic acidosis, renal failure, rhabdomyolysis, cardiac failure, and cardiopulmonary arrest with potential fatal outcomes.

Tags: News