Why Acetadote

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I searched and couldn't find much. When I trained we were taught that IV NAC provided no benefits over PO. Now that Acetadote is out my PCC wants it every time (at great expense). Why does the Tox community feel that Acetadote is superior to PO NAC?

I was thinking because of the stink of NAC, due to the sulfur moiety. IV, you don't need to drop an NG, and/or the patients aren't puking up the med taken PO.

What if you could give activated charcoal IV? People would line up around the corner for that.

Originally Posted by Apollyon

I was thinking because of the stink of NAC, due to the sulfur moiety. IV, you don't need to drop an NG, and/or the patients aren't puking up the med taken PO.

What if you could give activated charcoal IV? People would line up around the corner for that.

That's what I do. Is that not the current thing?

Originally Posted by docB

I searched and couldn't find much. When I trained we were taught that IV NAC provided no benefits over PO. Now that Acetadote is out my PCC wants it every time (at great expense). Why does the Tox community feel that Acetadote is superior to PO NAC?

This is somewhat situational. If the patient is awake/alert, tolerating PO, and can knock back the PO NAC, then I say "down the hatch." Also, given that PO doses are primarily delivered to the liver due to first-pass effect, it theoretically is preferred. Pt compliance is a *big* issue though, so be liberal with the antiemetics.

Now, if the patient isn't like this, then IV is the way to go. If they're presenting late, then IV is the way to go --> more likely sick, more likely to need a prolonged course; and the studies showing benefit from NAC in people outside the original treatment window are done with IV NAC.

Another consideration is pregnancy; if they're pregnant, then due to the hepatic first-pass effect, there is potentially a lower delivered dose to the placenta... so theoretically, IV NAC is preferred.

Finally, charcoal adsorbs NAC; if you're giving AC along with NAC, the NAC *has to be* intravenous or else you don't derive any benefit from it.

Overall, though, I personally don't have a preference for either - APAP overdoses need NAC, and I'm not particular about how it happens... in the non-pregnant, single-ingestion, early-presenting patient who's not getting activated charcoal.

Cheers!
-t

Isn't AC on the way out?

Originally Posted by docB

Why does the Tox community feel that Acetadote is superior to PO NAC?

My preference, and that of our group, is the oral route. IV is for those who can't tolerate oral NAC after multiple antiemetics, pregnancy, liver failure or LFTs over a 1000.

Originally Posted by docB

Isn't AC on the way out?

I don't think so; but in my opinion AC is a targeted intervention...

It should be 'out' in terms of throwing AC at every overdose as a general knee-jerk reaction; but I believe it to be efficacious in specific situations.

-d

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because po NAC has been out of stock for months now? (at least at my current place)

Ever since I had the pleasure of drinking NAC on a tox rotation I show no mercy in recommending it. And I have been emphatic with my nurses on not talking about how gross it is in front of the patients. It's salty. Hold your nose. It's not that bad.

My favorite trick: Take juice box or the juice cups with the foil lids. Draw up NAC in syringe, pierce foil with needle and push NAC into juice. put straw through same hole. Lack of NAC fumes = lack of NAC smell = almost tasteless.

I've also found that activated charcoal goes incredibly well in chocolate milk.

I still have yet to try PO. When I did a tox month, we always gave IV (attending said it was preferred and more beneficial because most patients end up vomiting). I have not had a cooperative acetaminophen toxicity yet either.

These are all really great points! In addition, IV Acetadote only requires a 21 hr dosing regimen as opposed to PO NAC which traditionally requires 72 h hour dosing = Much longer inpatient stay! (Although, I do believe there are some studies using PO NAC for less time by monitoring serum APAP levels, but as far as I know or have seen in practice, 72h is still the "standard").

Originally Posted by AvocadoLover

IV Acetadote only requires a 21 hr dosing regimen as opposed to PO NAC which traditionally requires 72 h hour dosing

Keep in mind that when you get 2 Toxicologists talking about the "correct" treatment of acetaminophen, there is a good chance you will get 3 opinions.

The 21 hour dosing protocol is controversial subject. Personally, I don't use it as a "set it and forget it" way of doing things. I can also say that I have not treated for 72 hours with oral in a simple, uncomplicated, acetaminophen ingestion ever. I've always chosen a patient tailored approach. When using the 21 hour protocol, you kind of "get away with it," where as with the 72 hour oral, you are clearly using too much.

What do I mean:

It requires an understanding of what is going on physiologically: APAP goes to NAPQI which conducts an electrophilic attack on membranes. Glutathione quenches. As the amount of APAP ingested goes up, the amount of NAPQI produced also goes up, especially as other mechanisms of detoxification are swamped.

Seems simple, but it is unfortunately more complex than that. As time progresses from t=0, the injured liver membranes start an inflammatory cascade. Additionally, the membrane components can also become reactive (similarly to free radical propagation). There is growing evidence that some of the liver injury comes not from from the direct attack of NAPQI, but from products of the attack and the induced inflammation.

So, what does that mean? From a simplistic approach, if 1 mol of APAP forms 1 mol of NAPQI, you need 1 mol of NAC to regenerate 1 mol of glutathione to quench it. On a mg-mg basis, you need about 8% more NAC than APAP for a 1-1 quench. So the Acetadote protocol provides 300 mg/kg of NAC, so it can cover pretty much any ingestion of 275 mg/kg or more is covered. Plus, we know that a liver can realistically take 150 mg/kg (probably closer to 200 mg/kg) without resulting in transplantation. So, the Acetadote protocol, in the most simplistic form, should cover an ingestion up to 425 mg/kg. That very simplistic however.

More realistically however, an early presenting patient (< 8 hours) with normal LFT and otherwise normal protoplasm can probably be treated with the simplistic Acetadote as long as they haven't taken a massive dose. What is massive? I dunno. Maybe less than 300-350 mg/kg. Above those amounts, and, based on half life calculations, you run out of NAC before you run out of APAP. Theoretically you should have normal glutathione stores at this point and can absorb 150mg/kg of APAP without concern. One need only go to the North American Congress of Clinical Toxiciology meeting to see at least one or two posters each year on "Acetadote Failures" (heck, I think I even did one of those as a fellow). Although, usually "treatment failure" is defined as an LFT bump and the patients have an uneventful course after "failing."

There are also other poorly understood mechanisms related to APAP toxicity. Patients who have truly massive ingestions (> 1000 mg/kg) die very early, like on day 1 or 2. They don't die from liver failure but instead develop a severe lactic acidosis and refractory organ failure.

So what do my ramblings mean? Hard to say. For most early, uncomplicated APAP ingestions, you can get away with using the Acetadote protocol: there is probably enough NAC in there to neutralize the generated NAPQI, as most people don't take more than 300 mg/kg, and even if they have an LFT bump, it is unlikely to result in liver failure. If you don't check, you don't find it. The problem is that you can't rely on the protocol if the patient isn't early presenting, uncomplicated or if they took a lot. Outside of those limits and you have to worry about the other issues.

For most ingestions, using either the oral or IV, I check the LFTs and APAP at ~20 hours after treatment was started. If the LFTs are flat and the APAP < 10, I'm done. If there LFTs are rising or the APAP is detectable, I'm going to keep going for another 12-24 hours with either. Using the oral product, even with several doses of Zofran, is way cheaper than the IV.

On NAC vomiting: It is rare that a patient can't drink the NAC. The stuff has minimal taste and it is the smell that really does it. The other thing people forget is that NAC is around 1500 mosm. You put that in to the stomach undiluted and it will be returned to sender based on the osmolarity alone. Dilute that 4:1 in something cold and sweet combined with nose holding, a covered cup, straw and zofran and it almost always goes down.

Man, that was a fantastic post. Thanks!

Dear Mods:
Stickify this thread.

Dear BADMD:
Coolest co-advisor ever. d=)

Cheers!
-d

Thanks BADMD! :-)

Originally Posted by njac

because po NAC has been out of stock for months now? (at least at my current place)

Ever since I had the pleasure of drinking NAC on a tox rotation I show no mercy in recommending it. And I have been emphatic with my nurses on not talking about how gross it is in front of the patients. It's salty. Hold your nose. It's not that bad.

My favorite trick: Take juice box or the juice cups with the foil lids. Draw up NAC in syringe, pierce foil with needle and push NAC into juice. put straw through same hole. Lack of NAC fumes = lack of NAC smell = almost tasteless.

I've also found that activated charcoal goes incredibly well in chocolate milk.

I love reading about your tips...the things they don't teach you in pharmacy school... Thank you.