Pauline Anderson

December 15, 2015

PHILADELPHIA — Ketamine, used for analgesia and sedation in the hospital setting, is increasingly being used to treat refractory status epilepticus (RSE), but only for the most critically ill children, a new study of billing information shows.

Along with other research suggesting that ketamine is effective in controlling seizures in children with RSE and has a relatively benign adverse-effect profile, the new study results are a "call to action" to design a prospective study to determine the role of ketamine for RSE, said Zachary Grinspan, MD, Komansky Center for Children's Health, New York-Presbyterian/Weill Cornell Medical College.

He reported the findings during the American Epilepsy Society (AES) 69th Annual Meeting.

Dr Zachary Grinspan

The standard protocol for treating status epilepticus involves using benzodiazepines as a first-line therapy. For some children who are still seizing, various well-studied antiepilepsy drugs will stop the seizures. Although pentobarbital is effective, it's linked to dangerously low blood pressure, and some patients, despite receiving such a powerful medication, continue to seize.

When these medications fail, it's uncertain what the next step should be, even though finding a drug to stop seizures is critical at this stage to prevent devastating neurologic consequences, and potentially death.

The new research suggests that more doctors are turning to ketamine, a medication routinely used in-hospital in the general pediatrics setting.

Researchers from New York Presbyterian Hospital, Sanford (SD) Children's Hospital, and Boston Children's Hospital used the Pediatric Hospital Information System database, which collects billing information from 45 children's hospitals across the country.

From these data, they developed an algorithm that correctly identified cases of RSE.

They found that 48 children, ranging in age from 2 to 11 years, were treated with both pentobarbital and ketamine from 2010 to 2014. During that time, the number of hospitals using ketamine increased from 4 to 14, and the number of cases of ketamine use per year rose from 4 to 17.

Sickest Kids

Doctors didn't administer the drug until about day 11 of hospitalization, after first trying several other medications, said Dr Grinspan. "The children receiving ketamine are the sickest, most critically ill and challenging cases."

The suggestion is that they're the sickest because doctors waited until other agents failed before administering ketamine.

Dr Grinspan reported that the children receiving ketamine were in the hospital an average of 51 days, in the intensive care unit for 29 days, and on a ventilator for 30 days and required 24 days of electroencephalographic monitoring.

They also required vasopressor support for dangerously low blood pressure for on average 8 days. Of the 48 patients, 29% died.

The study doesn't explain why doctors are using more ketamine for RSE, but case reports published over the past several years indicate that ketamine has worked very well and quickly in RSE, the researchers suggest.

The study also didn't address whether ketamine works better than other options.

But ketamine appears to have several advantages. For example, it doesn't lower blood pressure to dangerous levels. In fact, said Dr Grinspan, there appear to be few adverse effects when the drug is used for RSE.

Despite some encouraging research, however, it's not likely that ketamine will become a first-line therapy. "Pentobarbital, despite its side effects, does shut down seizures and it works," said Dr Grinspan. "While ketamine shows promise for maybe moving up in the chain, we want to be careful and cautious and make sure that if we change our practice, that we do so based on evidence."

Continuous vs Intermittent Therapy

Ketamine, which is primarily an N-methyl-D-aspartate receptor antagonist, is typically delivered in a continuous intravenous infusion. Other research reported at the AES meeting showed that continuous antiepileptic therapy may not be appropriate for children with RSE.

That 2-year study included 111 patients with RSE at nine pediatric tertiary care hospitals in the United States. Half the patients received continuous therapy and half received intermittent therapy.

In patients with seizures lasting more than 30 minutes, it took longer to control the seizures in those getting continuous infusions than those receiving intermittent dosing, said Kevin Chapman, MD, associate professor, neurology, Children's Hospital Colorado, Aurora.

Dr Chapman also reported that the morbidity rate was higher in the continuous group than the intermittent group and that the former spent more time in the intensive care unit (10 days vs 2 days). All three patients who died were receiving continuous infusions, he said.

Dr Grinspan receives research support from the Centers for Disease Control and Prevention, the New York State Department of Health, the Nanette Laitman Clinical Scholars Program, and the Pediatric Epilepsy Research Foundation.  He has consulted for the US Department of Justice and for Supernus Pharmaceuticals. Dr Chapman's study was funded by an AES/Epilepsy Foundation of America infrastructure award.

American Epilepsy Society (AES) 69th Annual Meeting. Abstracts 3.177 and 1.123.

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