What is the clinical relevance of a case in which ketamine put a quick stop to seizures while stabilizing blood pressure in a man with severe pneumonia and in the throes of refractory status epilepticus?
To Robert Orman, MD, an emergency physician in Portland, OR, the -report quite possibly puts “another arrow in the quiver” when faced with such a challenging clinical case. To the author of the case report, it fosters hope that this approach will be tested in a clinical trial. (Neurocrit Care 2012;16:299.) And to a physician who helped compile a seminal study of ketamine in epilepsy almost 40 years ago, it may provide a reason to feel somewhat vindicated after the idea was initially disparaged.
In fact, if refractory status epilepticus (SE) occurred only rarely among patients in the emergency department, it probably wouldn't be a relatively -intense topic of debate, but currently the chance of seizure control actually declines with successive drug treatment. (Neurology 2012;78:1548.)
So single case reports keep accruing, in part because no large clinical -trials are providing side-by-side comparisons of treatment approaches. (Neurol Clin 2010;28:853.)
Dr. Orman stressed, however, that a case report is just that, “still an n of one,” as he put it. This latest case report, however, puts “ketamine down as another arrow in the quiver as a potential third-line agent, a single arrow among many,” he said.
Any finding based on one individual speaks to the "the problem with case reports," which may offer evidence of the potential for more study but no scientifically valid reason for altering treatment protocols, agreed Andreas Kramer, MD, MSc, a clinical assistant professor of critical care medicine at the University of Calgary in Canada, who wrote the case report. Only clinical trials will help answer such questions, he stressed, though he noted in his case report, that “it is conceivable that ketamine may be relatively more effective at treating refractory SE attributable to certain conditions.”
The patient he described was able to avoid anesthetic — and the possible risk from it — as well as the need for increased doses of first-line treatment for refractory SE, midazolam and propofol. Traditionally, agents such as these would be used in a patient who has refractory SE like this one at incrementally higher amounts. But doing so likely would have increased the patient's hypotensive state, Dr. Kramer noted.
His account arrives four years after a similar German case report showed the same result. (Epilepsy Res 2008;82[2–3]:219.) Between those two single-case accounts, several others have appeared, but many have been embedded in reviews on SE and are anecdotal. In fact, the selection of epilepsy treatment can constitute such a conundrum that it prompted a recent editorial by two experts in the field who asked whether neurologists are “really data-driven” about therapy, and then concluded “we can, and should, do better.” (Neurology 2012;78:1194.)
Dr. Orman concurred. “A patient with SE is a real challenge to treat because sometimes the seizure doesn't stop after first-, second-, or even third-line agents,” he said.
He and Dr. Kramer, however, cautioned against extrapolating from the case report, although Dr. Kramer added that evidence shows ketamine is “much more blood pressure-sparing” than the alternative agents, which may not have had much impact on seizure activity anyway. And the patient, who was discharged a short time later, is “doing well,” Dr. Kramer added.
Why has ketamine administration been controversial? It has been linked with brain damage, but as Dr. Kramer observed, that association has turned up rarely. One explanation for that -adverse effect is that ketamine generally has been utilized late in the process, when patients have been experiencing seizure for many days. In contrast, recent cases have used it early in refractory SE.
In fact, back in 1974, ketamine was shown to have no such brain-damaging effects in groups of epileptic patients and healthy volunteers. (Report on Ketamine and Epilepsy at the 48th -Congress of the International Anesthesia Research Society; March 1974, San Francisco.)
Those many years ago, in a series of 33 patients, ketamine was found to be a plausible agent in hemodynamically unstable epileptic patients or those in need of emergency surgery. Nonetheless, the findings were vigorously challenged, said Mehrdad Tavakoli, MD, one of the authors of that study.
Assertions by other researchers at medical conferences that their line of research was controversial and studies suggesting risk to the brain led Dr. Tavakoli and his colleagues to go in other directions. Though his ketamine research on SE was “a long time ago,” he commended Dr. Kramer's work. -Refractory SE remains a clinical challenge, he said.
Unfortunately, that is true, said Dr. Orman, who was named clinical instructor of the year at Oregon Health Science University twice in the past decade and who produces “ERcast,” a podcast that covers ED issues on the Internet. (See FastLinks.) Ketamine shouldn't be discounted in refractory SE because “when your pockets are empty of all the usual therapies, and you're looking around the room to see if there are any other ideas of what do, the answer is sometimes found in a case -report,” he said. Saying “I heard of a case in Canada where ketamine was used for this” can be immensely helpful in such a situation, he noted.
“That being said, I think we need more data to figure out where ketamine belongs in a treatment algorithm and if it has negative effects,” Dr. Orman stressed.
Animal studies have shown in prolonged refractory SE that certain receptors, specifically GABAA, become internalized to neurons, removing them from the process of synapse, Dr. Kramer observed. This, in theory, is why propofol and midazolam, which succeed in seizure control initially, can lose effectiveness over time. Ketamine, in contrast, may work precisely because it counters receptors that increase during this process. Ketamine seems to be a powerful NMDA-receptor antagonist, Dr. Kramer explained.
“Mechanistically, ketamine makes sense in refractory SE,” agreed Dr. Orman.
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