Valproate for SE?

[Speculatrix]

I matched into medicine, but I was going through my old notebooks where I drew out pretty (but now useless) diagrams for all the different anticonvulsants and their mechanisms of action. The one thing I gleaned from that was valproate was a "swiss army knife" in the world of epilepsy treatment because there were so many mechanisms. Why isn't it at all in the algorithm for status epilepticus?

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[bluntdissector]

I matched into medicine, but I was going through my old notebooks where I drew out pretty (but now useless) diagrams for all the different anticonvulsants and their mechanisms of action. The one thing I gleaned from that was valproate was a "swiss army knife" in the world of epilepsy treatment because there were so many mechanisms. Why isn't it at all in the algorithm for status epilepticus?

It is, as far as I know IV valproate can be used as an alternative to phenytoin. Run a PubMed search and you should get loads!

Check here: http://faculty.neuroscience.ucla.edu/institution/publication-download?publication_id=224363

 

[typhoonegator]

We use it sometimes. However, as the above link to the review article points out, if you've gotten through multiple lorazepam doses and loaded phosphenytoin and you're still staring at a seizing patient, it's hard to try yet another drug load and wait to see if that works before starting midazolam or propofol. I'd rather get control of the situation and get the leads on before monkeying around further. Once you get them to stop, then you can use whatever makes sense for their seizure type and EEG pattern. Certainly, if intubation is going to take a few more minutes, a VPA load is probably worth a shot.

If they're on VPA at home (and it works), or VPA has broken long seizures in the past for a particular patient, I have no problem using it first to treat SE. The prospective data and high-level evidence is a bit better for PHT, assuming of course you've already tried the IV benzos. For pediatrics, there is some decent data to suggest that VPA is safe and effective at treating SE in kids as well (> 2 years old).

 

[Speculatrix]

gotten through multiple lorazepam doses and loaded phosphenytoin

That was sort of my question - why not jump from lorazepam to valproate as opposed to phosphentyoin?? I mean, if VPA has more mechanisms of action and seems much more "generalizable", why the VPA hatred in not going ativan->vpa as opposed to ativan->cerebyx. I assume they've been around for similar periods of time. I wanted to ask my neuro attending on my rotation so badly, but she kept pronouncing it "cerebrex" so I figured she wasn't the one to ask.

It seems to also be great for myoclonus, although that's just from empirical observation.

Thanks for the above article, very interesting!

 

[bluntdissector]

That was sort of my question - why not jump from lorazepam to valproate as opposed to phosphentyoin?? I mean, if VPA has more mechanisms of action and seems much more "generalizable", why the VPA hatred in not going ativan->vpa as opposed to ativan->cerebyx. I assume they've been around for similar periods of time. I wanted to ask my neuro attending on my rotation so badly, but she kept pronouncing it "cerebrex" so I figured she wasn't the one to ask.

It seems to also be great for myoclonus, although that's just from empirical observation.

Thanks for the above article, very interesting!

As typhoon said, it's a matter of data - phen has more data and is sortof part of 'dogma', so it will take a few studies to prove VPA is better. Check this pilot study:

Neurology. 2006 Jul 25;67(2):340-2.
Sodium valproate vs phenytoin in status epilepticus: a pilot study.

Misra UK, Kalita J, Patel R.
Sixty-eight patients with convulsive status epilepticus (SE) were randomly assigned to two groups to study the efficacy of sodium valproate (VPA) and phenytoin (PHT). Seizures were aborted in 66% in the VPA group and 42% in the PHT group. As a second choice in refractory patients, VPA was effective in 79% and PHT was effective in 25%. The side effects in the two groups did not differ. Sodium valproate may be preferred in convulsive SE because of its higher efficacy.

 

[ariwax]

depakote is a great drug for seizures, but i wouldn't use it first-line. for one thing, it causes more neural tube defects than other AED's when administered to women of reproductive age. it also can cause tremor, headache, sedation, weight gain, hyperammonemic encephalopathy, liver damage, blood dyscrasias and neuropsychiatric disturbances. if you start something for status, keep in mind that the patient will likely be continued on it long-term if it broke the seizure. side effects will compromise your pt's quality of life, as well as jeopardize medication compliance. and if your patient is a young woman of reproductive age, depakote is the last thing you want them taking, unless you enjoy being named in a malpractice suit.

of course, phenytoin is far from perfect for reasons of its own. I typically use IV Keppra instead: no need to check levels, no need to run a slow infusion, rapid time to onset, no hepatic metabolism, and minimal side effect profile (aside from the occasional pt who goes psychotic, which is unfortunate but goes away when the drug is stopped). also, reasonably safe in pregnancy, so far as the data goes.

 

[Head]

I think the reason that depakote comes after dilantin in the status algorithm is this urban legend that depakote may make seizures worse in a subset of patients with partial epilepsy syndromes. I think this may be true for some very rare congenital epilepsy syndromes, but I have never seen it in clinical practice.

To the poster that wants to use keppra instead of PHT, there is no data on it's use in status. I think from a medico-legal standpoint, you are obliged to use the benzos and load dilantin before trying something like keppra. At that point you could probably try keppra or depakote while getting them hooked up to LTM and heading towards pentobarb coma.

 

[bluntdissector]

I think the reason that depakote comes after dilantin in the status algorithm is this urban legend that depakote may make seizures worse in a subset of patients with partial epilepsy syndromes. I think this may be true for some very rare congenital epilepsy syndromes, but I have never seen it in clinical practice.

To the poster that wants to use keppra instead of PHT, there is no data on it's use in status. I think from a medico-legal standpoint, you are obliged to use the benzos and load dilantin before trying something like keppra. At that point you could probably try keppra or depakote while getting them hooked up to LTM and heading towards pentobarb coma.

Sorry to be such a anal PubMed-searcher, but there is quite a bit of data on keppra in status.

The only free 'article' I could find in such a short period of time is a commentary by Prof Hirsch from Columbia:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566612/pdf/epc0008-0125.pdf

But go here for some more.

 

[typhoonegator]

depakote is a great drug for seizures, but i wouldn't use it first-line. for one thing, it causes more neural tube defects than other AED's when administered to women of reproductive age. it also can cause tremor, headache, sedation, weight gain, hyperammonemic encephalopathy, liver damage, blood dyscrasias and neuropsychiatric disturbances. if you start something for status, keep in mind that the patient will likely be continued on it long-term if it broke the seizure. side effects will compromise your pt's quality of life, as well as jeopardize medication compliance. and if your patient is a young woman of reproductive age, depakote is the last thing you want them taking, unless you enjoy being named in a malpractice suit.

of course, phenytoin is far from perfect for reasons of its own. I typically use IV Keppra instead: no need to check levels, no need to run a slow infusion, rapid time to onset, no hepatic metabolism, and minimal side effect profile (aside from the occasional pt who goes psychotic, which is unfortunate but goes away when the drug is stopped). also, reasonably safe in pregnancy, so far as the data goes.

All valid issues for seizure ppx, but if the patient has been actively seizing for 45 minutes, I'm more worried about death and airway protection than tremor. I want to use the most efficacious drug, and while levetiracetam may be promising, it hasn't been proven superior in my opinion. You can always transition later -- no one says you HAVE to keep them on it.

 

[Speculatrix]

depakote is a great drug for seizures, but i wouldn't use it first-line. for one thing, it causes more neural tube defects than other AED's when administered to women of reproductive age. it also can cause tremor, headache, sedation, weight gain, hyperammonemic encephalopathy, liver damage, blood dyscrasias and neuropsychiatric disturbances. if you start something for status, keep in mind that the patient will likely be continued on it long-term if it broke the seizure. side effects will compromise your pt's quality of life, as well as jeopardize medication compliance. and if your patient is a young woman of reproductive age, depakote is the last thing you want them taking, unless you enjoy being named in a malpractice suit.

of course, phenytoin is far from perfect for reasons of its own. I typically use IV Keppra instead: no need to check levels, no need to run a slow infusion, rapid time to onset, no hepatic metabolism, and minimal side effect profile (aside from the occasional pt who goes psychotic, which is unfortunate but goes away when the drug is stopped). also, reasonably safe in pregnancy, so far as the data goes.

Doesn't phentyoin have a whole set of problems for women of reproductive age as well?? I remember being told this as a reason as well, but what about the (very real) stuff we learned about the fetal hydantoin syndrome? I'm going off pure memory but doesn't the neural tube close by the 4th week? However, phenytoin messes up development throughout the pregnancy, I thought. And if you're talking about keeping a woman on a drug for life... phenytoin? With the coarsening of facies, hirsutism, gingival hyperplasia, etc.? And it should have similar hepatotoxicity, cerebellar atrophy... blood dyscrasias - what about a megaloblastic anemia? I'd rather load her with depacon if I had to choose b/w it and dilantin/cerebyx. And lawsuit wise, I'd assume I'd be hit with it even if I loaded dilantin because of that hydantoin syndrome.

Though I have nothing to do with neurology, I have actually seen someone stay permanently bipolar/manic and turn into an irritable bitch after taking keppra. I also thought it was not FDA approved for status epilepticus? I mean, we do so much that isn't FDA approved and which drug company has the time to go back to ask for more indications, and I'm sure with time Lexapro can get the same level of FDA-approved indications as Prozac for example. Even still, SE seems like a lucrative enough "condition" that the makers of Keppra ought to petition for approval for SE? Is there some negative to using it for SE? It doesn't seem like we know the exact mechanism of how this drug works (it doesn't seem to be channel-based)... people tried to give me the analogy of it being like the mute on a remote button, preventing bursts from being relayed.

 

[BlackFrancis33]

This is an interesting discussion. The long-term risks of fosphen and depakote are not a concern in the status setting obviously. IV Depakote ie Depacon is used for refractory status epilepticus as is IV Keppra. If a person seizes through 0.1 mg/kg total of lorazepam and 18-20 PE/kg of fosphenytoin then IV Depacon is an option third line over phenobarbital or 4th line after phenobarb or 4th line or greater if seizing through IV anesthetics. It does not have FDA indication but as stated above there is voluminous evidence that is Class II and below.

The problem with the IV Depacon studies is that many of them were done in patients already receiving IV fosphen. Depakote displaces phenytoin/fosphen from serum proteins so some argue that Depakote is effective in status becaus it frees up more fosphenytoin from serum proteins. I think this is being studied, can't say for sure, I don't follow this literature as closely. Any urban legend of worsening certain seizure types also applies to phenytoin and its derivatives particularly myoclonic, absence, and primary generalized seizures and by extrapolation the associated status syndromes in each of these seizure types.

IV Depacon is a great option in status as you can 'slam it in' up to 200 mg/kg/min. You can also load IV Depakote to a goal level using this formula 0.2 x wt in kg x (Goal serum level - current serum leve) = dose in milligrams to achieve goal serum level. In my experience ,this formula works really well. It also has only a single case report (I think) of causing hypotension compared to phen, fosphen and phenobarb all of which will lower BP. So this can be given to really sick patients, patients with drug- or toxin-induced status (if known) etc. You may be able to avoid intubation or at least prolonged intubation if you are able to avoid phenobarb.

I don't get paid by the company or anything, but I consider this an option third line after Lorazepam and fosphenytoin, or in addition to IV anesthetics in refractory SE. I also think it has a place second line in place of phenytoin/fosphen or phenobarb. in hypotensive or intoxicated patients although this is not an FDA approved indication, but the study quoted above in 2006 in neurology provides good evidence that this is a reasonable therapeutic option.