hyperammonemia/ Divalproex

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I have an inpatient on dival (3500 mg qd, level about 80) who has had low level, chronic elevated NH3 (30-40). Hep B+, get meds for seizure d/o. Over the past he has developed ataxia, apraxia, and severely altered MS. NH3 is now 184?? Divalproex is being replaced by keppra, but any ther ideas??

🙁
 
The hyperammonemia sounds like it's from the VPA. This isn't surprising considering his Hep B+ status. Does he have just the antibodies, surface antigen, or fulminant disease? Any other LFTs? PT/PTT would be nice. The MS changes sound like hepatic encephalopathy.

Make sure the tourniquet isn't too tight for too long, or that he's smoking...these cause increased NH3 levels. What other meds is he on? Some can cause hyperammonemia (loops, thiazides, etc.)

It's doubtful that keppra is going to hold him alone if he was on that dose of VPA. Assuming this is a big guy (>200 lbs) or refractory to be on that dose, you'll probably need to supplement so he doesn't seize again. Of course, we'd need more info.

Good luck.
 
LFT's normal. Slightly elevated blood glucose, but it is just on a standard lab order day, so no control over time etc.. Pt is on carbamazepine, olanzapine as well. Carb level is 8.4, olanz dose 7.5. Patient is 50+ y/o. Your Dx sounds right to me, but I am trying to talk the attending into getting rid of the VPA ASAP to see if nh3 stabilizes. I think he will be OK on CBZ and Keppra, so does neuro.

😱
 
Your patient likely has a urea cycle defect, therefore the VPA is the cause of the elevated serum ammonia levels. You could also try Topamax.
 
Big Lebowski said:
Your patient likely has a urea cycle defect, therefore the VPA is the cause of the elevated serum ammonia levels. You could also try Topamax.
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Doesn't Keppra take a long time titrate up? if that's the case, i would go with topamax as well.
 
I am more worried about the damage the elevated NH3 is doing at this point than a breakthrough seizure. Anyone ever use lactulose for elevated NH3?? 😕
 
psisci said:
I am more worried about the damage the elevated NH3 is doing at this point than a breakthrough seizure. Anyone ever use lactulose for elevated NH3?? 😕
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I have seen it used before on surgery when a pt has liver failure. I don't think that it is very complicated to use. Basically, lactulose stays in the GI tract for its effects and is not absorbed systematically.
 
psisci said:
I have an inpatient on dival (3500 mg qd, level about 80) who has had low level, chronic elevated NH3 (30-40). Hep B+, get meds for seizure d/o. Over the past he has developed ataxia, apraxia, and severely altered MS. NH3 is now 184?? Divalproex is being replaced by keppra, but any ther ideas??

🙁
Click to expand...

Important points (#2 & #5 being the most important!):

(1) Hyperammonemia does effect mental status, though -- importantly -- the absolute number is not as important as the change in the ammonia level. A person can get used to an ammonia level of 50, or 70, yet if they go from 30 to 70 rapidly, they will have an acute change in their mental status. (Think of it like ETOH and intoxication.) Therefore, don't always assume that hyperammonemia, if it is mild, is the reason for a change in mental status. In this case, though, the ammonia probably is the cause.

(2) Just being Hep B+ should not affect ammonia levels. What will affect ammonia levels is liver failure. He may be in liver failure even if the LFTs are normal! Remember, LFTs elevate as the liver gets worse over time, but when it becomes cirrhotic, the AST/ALT look normal because no more damage is being done. You need to check GGTP, PT/PTT or just a simple platelet count in a CBC. If any doubt, do an ultrasound.

(3) Depakote should be discontinued immediately whenever possible if there are any signs of hepatotoxicity, including hyperammonemia. He might have Depakote-induced hepatitis or hepatic failure, or Hep B-related hepatitis or liver failure, but in any case the Depakote will make it worse.

(4) Lactulose is an extremely safe way to treat hyperammonemia and should always be used for hyperammonemia unless there is a specific contraindication. It binds to the ammonia and takes it out of the body, resulting in diarrhea for the patient (and they will complain), but it works very effectively and quickly.

(5) To heck with the Keppra. Sure, go ahead and titrate whatever you want, but in the meantime, get this guy off the Depakote! Use Ativan to control seizures if you have to -- it's not metabolized in the liver and it's an old-fashioned, perfectly reasonable way to keep the seizure d/o under control while you wait for the neurologist to titrate up on whatever drugs s/he chooses.

Good luck.

Yours,
Purple-"former liver transplant psychiatrist"-doc
 
Thanks for the thoughtful and informative reply! I agree with all of your points. The problem I have is the attending is A) an older orthopedic surgeon??, and B) He is stuck between different consultants saying different things so he does nothing. The VPA is tapering but by 250 mg q week, and I wanted to go much quicker. The NH3 has dropped back to the 50's as of yesterday, but the pt is still very lethargic and in a wheelchair.
I take it you do not like Keppra; what are your thoughts?

😎
 
psisci said:
Thanks for the thoughtful and informative reply! I agree with all of your points. The problem I have is the attending is A) an older orthopedic surgeon??, and B) He is stuck between different consultants saying different things so he does nothing. The VPA is tapering but by 250 mg q week, and I wanted to go much quicker. The NH3 has dropped back to the 50's as of yesterday, but the pt is still very lethargic and in a wheelchair.
I take it you do not like Keppra; what are your thoughts?
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Actually, I have nothing against Keppra, and since it's renally excreted, is a good choice for someone with potential liver problems if their kidneys are functioning normally. It's just that the dosage needs to be increased slowly -- it can be raised by 1000 mg qd every 2 weeks -- and in the meantime, they're continuing to give the patient Depakote. So, my only thought was, stop the Depakote right away and use Ativan in the meantime if needed for seizure control while the Keppra is titrated upwards. Seizures can be controlled in the hospital and are not generally fatal; fulminant liver failure cannot be controlled and can be fatal.

Out of curiousity, a few more questions: (1) Who are the two different consultants (specialties, not names) and what are they recommending? (2) What is the guy inpatient for? (Orthopedic surgery?) (3) Is there any other evidence of liver failure or problems in the labs?

By the way, one other thing I didn't mention that is always important to check if you ever see elevated ammonia levels. The blood must be drawn and rapidly assayed or kept on ice until it can be. As the blood hemolyzes, ammonia will be released, artifically elevating ammonia levels on lab tests. Don't think it's relevant in this case -- just FYI.

Great learning case. Hope he's doing better.
 
psisci said:
...Pt is on carbamazepine, olanzapine as well. Carb level is 8.4, olanz dose 7.5.
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Oops! Didn't see this. Important additional points:

(1) Tegretol does commonly cause dizziness, drowsiness, or ataxia, though if level is within normal range, these should be mild. It is an inducer of CYP 450 enzymes 1A2, 3A4 and 2D6, among others. It is potentially hepatotoxic, and has caused hepatitis and even fulminant liver failure, though very rarely. Though it would be safest to discontinue it as well as the VPA if there are any signs of hepatotoxicity, it has so many drug interactions that this has to be done very carefully to avoid development of toxic levels of other medications. (See below.)

(2) Olanzapine, while a safe choice as an antipsychotic in liver failure, also lowers the seizure threshold, like other antipsychotics. Why is he on it? In terms of med interactions, coadministration of Tegretol will metabolize it faster (by 50%!) lowering the serum level of olanzapine. No problem combining it with Depakote, though olanzapine is definitely linked to pancreatitis and can cause elevated LFTs, leaving the doc to wonder which medicine needs to be stopped.

Are we having fun yet? 😀
 
OK check this out!!! This all started when this guy was put on Keppra 500 mg bid, and DVPA lowered by 250 mg qd. NH3 started going up, so I said to attending, "lower DVPA faster, re check NH3 daily". However, neuro had told attending a few days before to taper DVPA 250 mg q2weeks, so attending kept the order as written. NH3 shot up over 48 hours, and this prompted my original question. I asked attending to get a VPA level yesterday just to see.......and it was 160!! How the hell could he be stable on CBZ and DVPA doses, and when Keppra is added (renal excretion they say) his level doubles? DVPA was dropped 250 mg tid today, and NH3 is already back to 40's. Attending also ordered 10,11 epox for the CBZ due to ataxia, but that is not back yet.
This patient is developmentally disabled in a state hospital; he lives here. The attending is assigned by the medical director, and just happens to be an orthopod. BTW this guy is hep B surface antigen + only. We get some interesting pharm stuff here, I was mentioning to another member awhile back that I have a Kluver-Bucy patient here...thanks again.

🙂
 
psisci said:
OK check this out!!! This all started when this guy was put on Keppra 500 mg bid, and DVPA lowered by 250 mg qd. NH3 started going up, so I said to attending, "lower DVPA faster, re check NH3 daily". However, neuro had told attending a few days before to taper DVPA 250 mg q2weeks, so attending kept the order as written. NH3 shot up over 48 hours, and this prompted my original question. I asked attending to get a VPA level yesterday just to see.......and it was 160!! How the hell could he be stable on CBZ and DVPA doses, and when Keppra is added (renal excretion they say) his level doubles? DVPA was dropped 250 mg tid today, and NH3 is already back to 40's. Attending also ordered 10,11 epox for the CBZ due to ataxia, but that is not back yet.
This patient is developmentally disabled in a state hospital; he lives here. The attending is assigned by the medical director, and just happens to be an orthopod. BTW this guy is hep B surface antigen + only. We get some interesting pharm stuff here, I was mentioning to another member awhile back that I have a Kluver-Bucy patient here...thanks again.

🙂
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OK, I'm really intrigued. What were all the medications he was taking when this happened? And was the VPA lowered at the exact same time as the Keppra was started? Pharmacology mysteries are really interesting. (Well, to me, anyway.) Any co-morbid medical problems other than the epilepsy?

By the way, are you a med student, psychology intern, pharm student? I'm guessing not a psych resident, since you have to defer to the attending. Residents often do that in private hospitals with private patients, but rarely in state facilities, where the attendings are usually all to happy to leave the work to the residents. 🙂
 
This guy has tuberous sclerosis, generalized tonic-clonic seizures under good control, and a possible dementia process (recent). The only med changes that occured between labs were the reduction of the DVPA and the initiation of Keppra...weird.
I am not a student of any sort actually. I am on the medical staff here. Our system works by having a physician assigned to a unit/ward as attending; they are the gatekeepers, and the rest of us consult to them.

thanks 🙂
 
Then why not just d/c the depakote (why the need to taper? just keep him on seizure precautions; believe me, the neuro won't be offended, especially if you keep him in the loop by calling him and letting him know of what you're doing); d/c zyprexa too, no clear indication for it plus it may lower the sz tresh, -plus it's overloading the already hard working liver; keep him on the tegretol plus lactulose, and initiate kepra, if you want; monitor tegretol levels, ammonia levels, lft's. The clear benefits of being more decisive re. d/c meds seem to outweigh any potential risks in this case. Keep the neuro in the loop, since you're more aggressively involved now in the case. The ortho will be more than happy with someone else than him taking "charge". I know, I know...you're doing all the hard work, while everyone else is seemingly tweedling their thumbs. So what? This is not the time to be shy, indecisive, uncertain, passive-aggressive, fearful, upset at the "system", or whatever it is that's going on underneath it all. Take this with a grain of salt, I didn't mean to offend. I'm just thinking of the pt.'s needs most of all.
 
This is not a psych facility I am working in, so things are done in a very strange manner. Consultants are not supposed to write orders, although it does happen from time to time. I agree with you about not being reticent etc..., and I really have not been. The patient is stable now. There is a turf war here with certain meds between neuro and psych, and sometimes this is what happens..unfortunately. Thanks for everyone's input!!

😎
 
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