White oval shaped Acetaminophen tablets in a pile sitting on a grey counter.

ARE YOU UP-TO-DATE? TREATMENT CHANGES IN ACETAMINOPHEN OVERDOSE

Julie Weber Poison Alerts

Acetaminophen overdose is very common.  The antidote, n-acetylcysteine (NAC), given within 8 hours of ingestion prevents hepatotoxicity in most overdose cases by replenishing glutathione.  It still offers some benefit even if initiated later than 8 hours.  

A revolutionary change in NAC dosing was introduced about 5 years ago.  The problem was that the FDA-approved 21-hour, 3-dose regimen for intravenous NAC (Acetadote) uses 3 separate IV bags with different amounts and different concentrations of NAC in each bag.  This complex situation leads to frequent dosing and administration errors.  

The innovation that reduced these types of errors is the programmable infusion pump that uses a standardized IV bag with the same amount and concentration of NAC in each bag (hence the name, “one-bag method”).  The dose is individualized for each patient in one easy step at the bedside instead of multiple bags from the pharmacy and multiple bag changes at the bedside.

Most facilities further streamlined the one-bag regimen into 2 doses instead of 3 – after the loading dose, they continue maintenance therapy at the dose rate of the “middle bag” and never lower it to the rate of the “3rd bag.”

Currently, approximately half of the hospitals in Missouri still use the traditional 3-dose regimen, and half use the newer 2-dose regimen with programmable infusion pumps.

The management of acetaminophen overdose continues to evolve and has changed substantially over the last few years.  After thorough review of the literature, we have updated guidelines to include the best, most up-to-date recommendations.  Here are the most important updates.  

As always, for specific advice on individual patients or for more information about the newer acetaminophen treatment strategies, call the Missouri Poison Center at 1-800-222-1222.

 

UPDATE 1:  HIGHER MAINTENANCE DOSING FOR APAP LEVELS THAT PLOT ABOVE THE “300 LINE”

The Rumack-Matthew acetaminophen nomogram showing which patients are at higher risk for hepatotoxicity

Click image to enlarge.

Patients who plot above the “300 line” on the Rumack-Matthew nomogram are at higher risk for hepatotoxicity. These patients should receive the dose rate in the 2nd bag (12.5 mg/kg per hour) for the entire 20-hour maintenance dosing of the initial course of therapy.  Facilities that use the one-bag regimen are already treating all patients with a higher maintenance dose, so adjustment is not usually necessary.  However, if the traditional 3-dose regimen is being used, the patient should receive a “prolonged middle bag.” In other words, the traditional regimen is converted into a 2-bag/2-dose therapy.  This higher maintenance dosing better matches the antidote dose to the higher acetaminophen level. 

If NAC therapy is extended beyond the 21-hour initial regimen, the dose rate can be reduced to 6.25 mg/kg per hour, which is the usual dose rate of the 3rd bag. Alternatively, it is also acceptable to stay on the 2nd bag dose rate (12.5 mg/kg per hour) for the entire duration of NAC therapy.

 

UPDATE 2: CONSIDER TREATMENT WITH A 2-BAG/2-DOSE “SLOW-LOAD” REGIMEN

This regimen administers the loading dose over 4 hours instead of the traditional 1 hour and has been shown to be as effective as the rapid load in comparative clinical trials.  A slow-load regimen minimizes the incidence of adverse effects, which are related to histamine release.  If a patient has already developed an adverse reaction to the standard 1 hour loading dose, such as urticaria, pruritus, or angioedema, treat with diphenhydramine and consider switching to the a slow-load regimen once symptoms resolve.  Restart NAC no later than 1 hour after stopping.  Some facilities use this regimen as their primary protocol for acetaminophen overdose in all patients.

The slow-load be followed by either a LOW maintenance dose or a HIGH maintenance dose. 

  • Option #1: LOW Maintenance Dose: Loading dose of 50 mg/kg per hour for 4 hours, followed by 6.25 mg/kg per hour for 16 hours (300 mg/kg total) 

OR

  • Option #2: HIGH Maintenance Dose: Loading dose of 50 mg/kg per hour for 4 hours, followed by 12.5 mg/kg per hour for 16 hours (400 mg/kg total) 

 

UPDATE 3: ORAL NAC IS STILL A GOOD OPTION FOR TREATMENT

Oral n-acetylcysteine may have fallen out of favor in many facilities due to the convenience of IV administration; however, it is still a viable treatment option.  Oral NAC is equally effective as IV NAC and can be substituted for IV NAC in all indications.  Histamine-release reactions are less common, and the drug cost is considerably lower.  Nausea and vomiting are not as common as the drug’s odor might suggest and can be handled by ondansetron if they occur.

Don’t be put off by the historical regimen of giving 17 maintenance doses.  It is acceptable to dose the oral regimen for only 20 hours in an acute overdose, the same duration as the IV regimen. Treat with an initial loading dose of 140 mg/kg, followed by 5 maintenance doses of 70 mg/kg given every 4 hours.  If needed, based on repeat APAP and AST/ALT lab results, the oral regimen can be extended in increments of 3-4 maintenance doses at a time which provides another 12-16 hours of therapy.

Some of the most appropriate uses for oral NAC include: 

  • The patient arrives shortly after acute overdose and the practitioner wishes to start NAC before the 4-hour serum APAP level is done.  There is no further dosing needed if the initial (4-hour) APAP level is non-toxic (below the 150-Line/Treatment Line). 
    • However, if the level plots above the 150-line, either IV or oral maintenance dosing can be started, as appropriate, according to where the APAP level falls in the nomogram.
  • The serum APAP level after acute overdose is between the 150-Line/Treatment Line and the 200-Line/Risk Line on the nomogram AND the patient is not vomiting.
  • The patient has serum APAP > 20 mcg/mL  OR  ALT > 50 after one of several patterns of repeated supra-therapeutic dosing AND the patient is not vomiting. 
  • The patient had a histamine-release reaction to IV NAC beyond simple flushing and nausea.

 

UPDATE 4:  WHEN TO DISCONTINUE NAC 

This has become a very complicated decision, and a very good reason to engage the Missouri Poison Center in the care of your APAP overdose cases.  Every patient needs an individualized decision.  This is how our written guideline puts it. 

Obtain AST/ALT and serum APAP level at the same time, 2 hours prior to the completion of IV NAC therapy or after the 5th maintenance dose of the oral regimen. ALT is more specific for hepatocellular injury and is used to determine the degree of toxic injury and to plan subsequent interventions. AST rises and falls faster and is a better indicator of the time course of injury and recovery. 

The initial 21-hour course of NAC can be stopped if:

  1. The serum APAP level is < 10 mcg/mL or “non-detect” AND 
  2. ALT is either about the same or lower than the baseline, OR 
  3. ALT has risen from a normal baseline to no higher than 100 units. 

If these criteria are NOT met, continue APAP for another 12-16 hours.  

Two hours before the end of the 1st extension or after the last oral dose in the extension, repeat AST/ALT and serum APAP level to determine if NAC should be extended.  Note: Once the APAP level is <10 mcg/mL it does not need to be repeated. 

IMPORTANT:  If the ALT is > 1000 units, extend either IV or oral NAC continuously, and begin additional monitoring as below.  Continuous NAC can be discontinued when AST and/or ALT have peaked and are clearly trending downward, INR is normalizing, and the patient is improving.  AST will decrease first.  

The 1st extension of NAC can be stopped after 12-16 hours (~33-37 hr total dosing), if:

  1. The previous or current APAP level is < 10 mcg/mL or “non-detect” AND
  2. The current ALT is about the same or lower than the previous value (Elevations < 50 units or < 10% are not significant), OR 
  3. The current ALT has risen from a normal baseline to no higher than 150 units.

If these criteria are NOT met, continue APAP for another 12-16 hours and begin additional monitoring:

Start or continue to monitor the patient’s mental status, acid-base status, renal function, glucose, and PT/INR to assess overall status of liver function. Also, two hours before the end of the second extension of NAC dosing or after the last oral dose in the extension, repeat AST/ALT.  Repeat serum APAP level only if the previous level was > 10 mcg/mL.

IMPORTANT:  If the ALT is > 1000 units, extend either IV or oral NAC continuously, and begin additional monitoring as below.  Continuous NAC can be discontinued when AST and/or ALT have peaked and are clearly trending downward, INR is normalizing, and the patient is improving.  AST will decrease first.

The 2nd extension of NAC can be stopped after 12-16 hours (~45-53 hr total dosing), if:

  1. The current ALT is about the same or lower than the previous value, OR
  2. The current ALT has continued to rise but is still not more than double baseline AND
  3. The current ALT is still < 1,000 units.

Monitor AST/ALT every 6 to 12 hours, depending on the patient’s condition. Start or continue to monitor the patient’s mental status, acid-base status, renal function, glucose, and PT/INR to assess overall status of liver function.

NOTE!  Continuous NAC can be stopped when:

AST and/or ALT have peaked and are clearly trending downward, INR is normalizing, and the patient is improving. AST will decrease first. AST/ALT do not have to be < 1,000 units to stop continuous NAC.

 

If you have a patient with acetaminophen overdose, please call the Missouri Poison Center at 1-800-222-1222 where specially trained nurses, pharmacists, and medical toxicologist can provide you with the most up-to-date management advice on common and uncommon exposures.

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