Volume I:
First Thirty Minutes
- Section 1
  Acute Care Algorithm/ Treatment Plans/ Acronyms
- Section 2
  Universal Approach
  - CALS Universal Approach To Emergency Advanced Life Support
- Section 3
  Steps 1-6
- Section 4
  Preliminary Impression/Focused Clinical Pathways
Volume II:
Resuscitation Procedures
Volume III:
Definitive Care

Toxicology 3: Acetaminophen Overdose Portal

Management of Common Poisoning/Overdose

A common overdose is acetaminophen (APAP) ingestion. Severe and potentially fatal hepatotoxicity can result from APAP poisoning. Over 200 products contain APAP, and APAP can lead to significant toxicity if > 140 mg/kg is ingested. In adults and adolescents, hepatotoxicity may occur following ingestion of 7.5 grams (24 regular strength pills or 15 extra-strength pills). Fatality occurs in < 3% of untreated cases and is unlikely in overdoses of < 15 grams (45 regular strength or 30 extra-strength pills). PEDS: Serious toxicity has been uncommon in children under the age of 12 years. This is postulated to be due to a difference in APAP metabolism noted in children.

Initial Diagnostic Actions

As is typical for patients who are seen relatively early after potentially toxic acetaminophen ingestion, a paucity of symptoms assists in diagnosis. The patients may in fact be asymptomatic or have flu-like symptoms.

If you see the patient within 2 hours and the patient gives a history of significant APAP ingestion, give AC. You may obtain an APAP level. If this level is < 100 at 2 hours, it is doubtful that the patient has ingested a toxic amount. If the level at 2 hours is > 100, obtain a level at 4 hours.
If you see the patient within 4 to 8 hours, obtain an APAP. Treat with antidote N-Acetylcysteine (NAC) if the level falls on or above the potentially toxic line on the Rumack-Matthew Nomogram. (See Table 1, N-Acetylcysteine Antidotal Therapy and Figure 1, Rumack-Matthew Nomogram.) Give AC if the patient has a history of coingestion that may delay gastric emptying (diphenhydramine, TCA, ASA).
If you see the patient 8 hours post-ingestion and the patient has a history of potentially toxic ingestion, give NAC loading dose and obtain APAP level. If the level falls on or above the potentially toxic line on the Rumack-Matthew Nomogram, continue NAC treatment. If the level is below the line, discontinue NAC.
If you see the patient more than 16 hours post ingestion, obtain APAP level, AST, AMA-7, and begin NAC therapy. Continue therapy if the APAP level is above 5 to 10.

Initial Therapeutic Actions

Although patients may have a classic benign appearance, initially direct your attention toward stabilizing the patient's ABCs. It is always possible that the patient may have taken a potentially lethal co-ingestion of another product. Thus, take a systematic approach to the acutely poisoned or overdosed patient.

Once you find that the patient has a potentially toxic level of acetaminophen, place an intravenous line (NS lock for stable, non-critical patients) and prepare a 5% solution of NAC for the loading dose (140 mg/kg—see Table 1) to be administered orally. If the patient has an emesis within 30 minutes of the oral dose, repeat the full dose after administering an anti-emetic. If the patient tolerates this, continue NAC with maintenance doses (70 mg/kg) every 4 hours until a total of 17 doses are given. The patient should remain as an inpatient.

Table 1. N-Acetylcysteine Antidotal Therapy. Loading Dose of 140 mg/kg PO

			Loading Doses
Body weight	20%NAC	Diluent	5% Solution
kg	mL	mL	Total mL
100 to 110	75	225	300
90 to 99	70	210	280
80 to 89	65	195	260
70 to 79	55	165	220
60 to 69	50	150	200
50 to 59	40	120	160
40 to 49	35	105	140
30 to 39	30	90	120

The diluent is typically a cola, lemon-lime drink, or fruit juice.

Definition/Pathophysiology

The patient who takes a potentially toxic dose of acetaminophen is at risk for developing hepatotoxicity. Approximately 4% of acetaminophen is metabolized by the P450 Mixed Function Oxidase System (MFOS). A highly reactive intermediate metabolite is produced but is quickly detoxified by glutathione. Once glutathione stores are reduced to less than 30%, the acetaminophen metabolite, n-acetyl-p-benzoquinoneimine (NAPQI) leads to a centrilobular necrosis of hepatocytes and possibly hepatic failure with coma, renal failure, cerebral edema, and subsequent death. Drugs that induce the P450 MFOS (anticonvulsants, rifampin, and chronic alcoholism) enhance the risk of hepatotoxicity. With supportive care, < 5% of patients with significant APAP overdoses will die. When patients are seen after 24 hours, their risk for morbidity and death increases. The antidote NAC is essentially 100% effective when given within 8 hours. The mechanism of action as a detoxifying agent is primarily due to its role as a precursor for glutathione. Another mechanism is that NAC can provide a sulfate substrate for the metabolism of excess APAP into non-toxic intermediaries.

Once patients have been started on the antidote, monitor their liver function tests. No further APAP levels are required once an initial toxic level is obtained.

If the patient vomits and is unable to retain the NAC, antiemetics may be administered. If vomiting persists, or if the patient is unable or unwilling to take NAC orally, protocols for IV administration of NAC are available and appear to be relatively safe, simple, and effective. Contact your poison center for specifics.

Currently, no FDA-approved intravenous preparation of NAC is available. Intravenous administration of the oral preparation filtered through a 0.22 micron filter has frequently been tried with success and minimal side effects.

4_tox_3_A

The Rumack-Matthew nomogram for single acute acetaminophen overdose/ ingestion. The upper line characterizes serum acetaminophen levels associated with hepatotoxicity. The lower line is a 25% allowance for possible errors in history and laboratory analysis.

Addendum to Acetaminophen Overdose Portal

In the United States, the only Mucomyst (N-Acetylcysteine [NAC]) treatment regimen currently approved by the Food and Drug Administration (FDA) for the treatment of APAP overdose is the standard 72-hour oral course consisting of 1330 mg/kg (total dose).¹Due to the “rotten egg” taste and odor of NAC, nausea and vomiting frequently occur when NAC is given PO. In situations where oral administration is unsuccessful (see additional considerations, page 6 this portal), administration by continuous IV infusion may be considered. Consult with a medical toxicologist or Poison Control before beginning the infusion.

Indications
Indications for the use of NAC IV administration include a high-risk patient who meets the following conditions^2,3:

Has intractable vomiting and thus cannot tolerate oral NAC but delay in treatment will result in a decrease in the efficacy of NAC (eg, beyond 10 hours post ingestion);
Has persistent vomiting in spite of attempted suppression (see Adverse reactions);
Presents late with increased protime (PT) or liver function tests (extrapolation indicated);
Has fulminant liver failure (the efficacy of NAC orally has not been studied, and NAC IV achieves higher serum concentrations than oral dosing);
Is pregnant (NAC IV achieves higher placental levels and may facilitate transplacental delivery to the fetus, but the advantage of NAC IV is only theoretical); or
Has a medical condition that precludes the use of oral NAC (eg, GI bleeding, GI obstruction, corrosive ingestion).

Adverse reactions to NAC IV
Administration of NAC IV has a reported adverse reaction incidence of 0.2% to 21%.³While some patients report nausea due to NAC IV, more serious adverse reactions to NAC IV are anaphylactoid and are dose-dependent, primarily occurring during the initial hour of loading therapy when serum levels are highest.³ While the most common features of anaphylactoid reactions are rash, urticaria, flushing, chills, and fever⁴; more serious reactions include angioedema, hypotension, bronchospasm, and, rarely, cardiovascular collapse.³ Discontinuation of the infusion of NAC IV and treatment with diphenhydramine IV is usually all that is required to treat the adverse reactions.³ Except with the occurrence of life-threatening reactions, the NAC IV may then be resumed at a slower infusion rate once the reaction has improved.³

NAC IV Therapy:
Note: NAC IV is not FDA approved. NAC products available in this country are labeled as sterile but not as pyrogen-free. Therefore, NAC IV solutions must be filtered through a 0.22-micron filter.

NAC IV Therapy Protocol for Adults (using the Prescott Protocol):^2,5

Initial loading dose: give NAC 150 mg/kg IV in 200 mL of D₅W over 30-60 min.
Then, administer NAC 50 mg/kg IV in 500 mL of D₅W by continuous infusion over 4 hours.
Then, administer NAC 100 mg/kg IV in 1000 mL of D₅W by continuous infusion over 16 hours
Minimum total dosing time = 20 hours plus the initial loading dose time.
Continue the NAC IV until all of the following completion criteria are met:
- The AST is less than 1000 IU/L,
- APAP is undetectable (<10 µg/mL, confirmed by a second APAP level),
- The patient is asymptomatic, and
- The NAC IV therapy has been administered for a minimum of 20 hours.

PEDS: Intravenous NAC Therapy Protocol for Children:²

If the use of NAC IV is deemed necessary, consult with Poison Control or a medical toxicologist before proceeding.

Initial loading dose: Give 150 mg/kg of NAC in either NS or D₅W in a total volume equal to 10 mL/kg over 15-30 min. (If flushing and itching occurs, slow the infusion rate and give over 30-60 min.)
Then administer 50 mg/kg NAC over a 4-hour period of time given in a maintenance IV volume. (See chart that follows for calculation of maintenance IV fluid volume).
Then administer 100 mg/kg NAC IV over a 16-hour period of time given in a maintenance volume. (See chart that follows for calculation of maintenance fluid volume).
Continue the NAC IV until all of the completion criteria are met (see previous).

Calculation of pediatric IV maintenance fluid volume based on the patient’s weight in kg:

4 mL/kg/h for the first 10 kg
2 mL/kg/h for the second 10 kg
1 mL/kg/h for each additional kg

Example: Calculation of NAC dose and IV fluid volume for a 25 kg child:
Maintenance IV fluid per hour = 65 mL/h [(4 x 10) + (2 x 10) + (1 x 5)]

NAC Administration:
Loading dose: 150 mg/kg x 25 kg = 3750 mg NAC in 250 mL IV fluid given over 30-60 minutes, then
Initial maintenance: 50 mg/kg x 25 kg = 1250 mg NAC in 260 mL IV fluid given over 4 hours, then
Continued maintenance: 100 mg/kg x 25 kg = 2500 mg NAC in 1040 mL IV fluid given over 16 hours.

Additional Considerations in the Treatment of Acetaminophen Overdose with NAC:

If activated charcoal is given, the loading dose of oral NAC does not need to be increased.
Some patients with increased risk of hepatotoxicity may need treatment with NAC for APAP overdose, even if their APAP level falls below the nomogram line. When alcoholics or patients taking enzyme-inducing medications (rifampin, anticonvulsants, or sufonylureas) present with APAP overdoses, consult a medical toxicologist for special considerations in their treatment. For patients at increased risk of hepatotoxicity, upon admission obtain the following lab tests: PT, CBC, AST, ALT, total bilirubin, basic metabolic profile, and urinalysis.
If the patient has ingested extended release acetaminophen, a second plasma APAP level 4 to 6 hours after the first level may be considered to be sure that the true maximum APAP serum level is obtained and that appropriate treatment with NAC is performed. Consult with Poison Control or your medical toxicologist if you have any questions.
To manage nausea and vomiting caused by oral administration of NAC (rather than administer IV):^2,3
- Dilute oral NAC with soda or fruit juice to a 5% solution.
- Chill the oral solution with ice.
- Sip the solution slowly with a straw from a sealed container.
- Slowly administer the oral solution via an NG tube.
- Use antiemetic drugs:

References

Smilkstein, MJ, Knapp, GL, Kulig, KW, Rumack, BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen poisoning.N Engl J Med. 1988;319:1557.
Minnesota Poison Control System, Hennepin Regional Poison Center.
Burns, MJ, et al. Management of acetaminophen (paracetamol) intoxication. In UpToDate, Wellesley, MA, 2002.
Smilkstein MJ, et al. Acetaminophen overdose: a 48-hour N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20(10):1058-63.
Prescott LF, et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning.Br Med J. 1979;2(6198):1097-100.