ARTICLE IN BRIEF
Investigators reported that patients with status epilepticus receiving intravenous anesthetic drugs (IVADs) had a higher proportion of infection and an increased risk of death compared with patients not receiving IVADs.
For decades, neurologists and emergency medicine physicians have been prescribing intravenous anesthetics to stop status epilepticus (SE) when first and second-line treatments fail. Now, a retrospective study published in the Dec. 6 online edition of Neurology suggests that the use of IV anesthetic drugs (IVADs) to stop these life-threatening seizures increased the risk of death nearly three-fold compared with patients who did not receive the treatment. Generally, physicians have been willing to risk using IV anesthetics, which often require intubation, to quiet the brain and stop the seizure.
“Until recently, we were convinced that putting refractory status epilepticus patients in a therapeutic coma was a good thing,” said Stephan Rüegg, MD, a neurointensivist at University Hospital in Basel, Switzerland. “We were astonished that anesthesia could increase mortality and we have been delivering this treatment for decades.”
Dr. Rüegg, in collaboration with Raoul Sutter, MD, and other colleagues in Basel, reviewed medical records to see how their patients with SE fared after treatment, controlling for factors other than the anesthetics that could have increased the patients' risk of dying.
During the study period — January 2005 to January 2011 — the standard protocol was to provide IV benzodiazepines and, if the seizure persisted, then doctors would administer second-line IV antiepileptic drugs (AEDs) such as phenytoin, valproate, or levetiracetam, Dr. Rüegg explained. If the second-line IV AEDs failed, the patients would be given other AEDs — third-line treatments — such as lacosamide, topiramate, vigabatrin, carbamazepine, and oxcarbazepine, with or without continuous infusions of IVADs (including midazolam, propofol, and barbiturates).
The investigators analyzed outcomes data on 171 patients with refractory SE — those who were treated with continuous IVADs (63) and those who were not (108); they excluded from their analysis patients whose seizures resulted from hypoxic encephalopathy after cardiac arrest.
Among findings, patients who received continuous IVADs had more infectious complications during the uncontrolled seizure activity than those who did not receive IVADs (43 percent vs. 11 percent, respectively; p<0.0001). A higher proportion of patients with IVADs died (30 percent versus 10 percent for those who did not receive IVADs; p<0.0001), with a 2.9-fold relative risk for death (RR 2.88; 95%CI 1.45-5.73) independent of possible confounders, including duration and severity of SE, non-anesthetic first-and second-line antiepileptic drugs, and critical medical conditions, the scientists said.
Those who were given IVADs had longer stays in the intensive care unit and hospital, as well as poorer outcomes. Of the deaths in the group that received the IVADs, five died during the prolonged seizure, two from multi-organ failure, and 11 from subsequent infections. The cause of death in one patient remained uncertain.
“Our findings should heighten awareness regarding adverse effects of IVADs,” and is a call to arms for neurologists treating these patients, said Dr. Rüegg. “We need randomized trials. We need to know which refractory patients would benefit from IVADs and who will be at higher risk of death,” he said. Right now, he added, “we are making these decisions by a gut feeling, but we really need to address this in a prospective trial.”
EXPERTS WEIGH IN
Several experts not involved with the research agreed that more randomized trials to study IVADs were needed, but they stopped short of support for forgoing the IVAD protocol to stop seizures.
“This study is a valuable attempt to provide some evidence to support treatments of these very sick patients and may provide some ethical support to randomize patients with refractory status epilepticus to more and less aggressive treatment protocols in future clinical trials,” said Jan Claassen, MD, PhD, assistant professor of neurology and director of the Neurocritical Care Training Program in the Division of Critical Care Neurology at Columbia University. “Clinically, it may provide some backing for physicians in certain cases of very frail patients to undertake a less aggressive approach such as IV valproate instead of a continuous anesthetic drip.”
However, Dr. Claassen said, it is possible that there were confounding factors that could have had an impact on the results. “Given the many limitations such as lack of randomization, a single center, and no comparison of a protocol change, there is a tremendous danger for selection bias. The authors made an attempt to control for baseline differences but the reasons why the primary physician at the time chose a continuous anesthetic drip is retrospectively impossible to determine. This may create an extremely misleading message based on highly skewed data that has potentially very deleterious effects.”
What's more, he said, “uncertainty exists regarding what the continuous anesthetic drip therapy should look like. There is not a uniform titration goal to seizure suppression, suppression burst, or complete suppression.”
He agreed that the study should spark a prospective randomized trial. But until there are more answers, he said, breaking the seizures as soon as possible should be the number one priority.
“The most rapid way that I know of to do so is by initiating a continuous anesthetic drip,” he said, “but this depends highly on the practice setting as continuous anesthetic drips may not be initiated in all settings such as some ERs, floor patients prior to ICU transfer, or in ambulances. If continuous anesthetic drips can be started in a safe setting such as an ICU or ER that is prepared to deal with the potential side effects such as hypotension, then this would be the preferred intervention that I would recommend.”
In an accompanying editorial, Nathan B. Fountain, MD, professor of neurology at the University of Virginia School of Medicine and director of the Comprehensive Epilepsy Program, and Jennifer Fugate, DO, an assistant professor of neurology in the Division of Critical Care Neurology at the Mayo Clinic in Rochester, MN, pointed out the important implications of the study.
“The results need to be interpreted cautiously, as the authors have done,” Dr. Fugate told Neurology Today in an interview. “The care of many patients will still require IV anesthetics, particularly in the setting of generalized status epilepticus. I think it may be important to discriminate the type of status epilepticus (generalized compared with focal) and underlying etiology, as the benefit-to-risk ratio for use of IV anesthetics may differ between these groups.”
Dr. Fountain noted that second-line treatment with standard antiepileptic drugs is usually pursued before anesthetics. Overall, about thirty percent of patients don't respond to first-line treatments, he said, and half of those who are given second-line treatments fail to respond and must be considered for IV anesthetics. However, there are still no randomized studies to determine which second-line treatment is best, before clinicians even consider anesthetics.
“It is too premature to advocate a change in clinical practice based on this study alone,” Dr. Fugate said, “and IV anesthetics will need to be prescribed in many cases. Perhaps in some clinical scenarios — such as focal status epilepticus — clinicians will be more inclined to try a third intermittent antiepileptic medication rather than going to IV anesthetics after the first and second-line treatments fail.”
She agreed that a prospective randomized study is needed, but also acknowledged that conducting such a trial could be complicated. “Phenytoin has been the standard treatment for convulsive status epilepticus where initial benzodiazepines have failed for many years, despite its many limitations in the emergency situation. Valproate and levetiracetam are emerging as potentially superior alternatives, and there is an urgent need for an adequately powered comparative randomized controlled trial.”
She noted that such a trial may be under way. “An international group is now preparing a revised proposal for submission to the National Institute of Neurological Disorders and Stroke to undertake a blinded comparative randomized controlled trial using an adaptive design,” Dr. Fugate said. “This will be an international and multicenter study requiring up to 1,500 patients from over 50 centers. The primary outcome, agreed from the 2009 status epilepticus workshop as pragmatic, generalizable, and clinically meaningful, will be cessation of seizures without need for other drug or sedation, and without serious adverse events, maintained for at least two hours.”
Such a trial, Dr. Fountain agreed, would pave the way for a future trial of anesthetics for refractory status epilepticus.