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Introduction

  1. Pharmacology. Acetylcysteine (N-acetylcysteine [NAC]) is the primary antidote for acetaminophen toxicity. It acts as a sulfhydryl group donor, substituting for the usual sulfhydryl donor of the liver, glutathione. It rapidly binds (detoxifies) the highly reactive electrophilic intermediates of metabolism, or it may enhance the reduction of the toxic intermediate, NAPQI, to the parent, acetaminophen. It is most effective in preventing acetaminophen-induced liver injury when given early after ingestion (within 8-10 hours), but it may also be of benefit in reducing the severity of liver injury by several proposed mechanisms (improved blood flow and oxygen delivery, modified cytokine production, free radical or oxygen scavenging), even when given after 24 hours. This proposed role of NAC as a glutathione precursor, direct sulfhydryl binding agent, and antioxidant has also been the basis for its investigational use for poisonings from agents that are associated with a free radical or oxidative stress mechanism of toxicity or that bind to sulfhydryl groups.
  2. Indications
    1. Acetaminophen overdose.
    2. Case reports of or investigational use in amatoxin-containing mushrooms, carbon tetrachloride, chloroform, acrylonitrile, doxorubicin, arsenic, gold, carbon monoxide, chromium, cyanide, nitrofurantoin, paraquat, and methyl mercury poisoning.
    3. Pennyroyal oil and clove oil poisoning (case reports). The mechanism of hepatic injury by pennyroyal oil and clove oil is similar to that of acetaminophen, and empiric use of NAC seems justified for any significant pennyroyal oil or clove oil ingestion.
    4. Cisplatin- or ifosfamide-induced nephrotoxicity and prevention of contrast-induced nephropathy.
    5. Pyroglutamic aciduria (5-oxoprolinuria).
    6. Non-acetaminophen-induced liver failure.
  3. Contraindications. Known acute hypersensitivity or IgE-mediated anaphylaxis (rare). Anaphylactoid reactions, although similar in clinical effects, may be prevented or ameliorated, as discussed below.
  4. Adverse effects
    1. NAC typically causes nausea and vomiting when given orally. Use of a gastric tube, slower rate of administration, and strong antiemetic agent (eg, metoclopramide, ondansetron) may be necessary.
    2. Rapid intravenous administration can cause flushing, rash, angioedema, hypotension, and bronchospasm (anaphylactoid reaction). Death (status epilepticus, intracranial hypertension) was reported in a 30-month-old child who accidentally received a massive dose intravenously (2,450 mg/kg over 6 hours, 45 minutes), and fatal bronchospasm occurred in an adult with severe asthma.
      1. Reactions may be reduced by giving the loading dose slowly (over at least 60 minutes) in a dilute (3-4%) solution and by exercising extra caution in patients with asthma (carefully titrate with more dilute solutions and slower infusion rates; pretreat with antihistamines).
      2. An additional risk factor for anaphylactoid reaction may be low serum levels of acetaminophen, whereas high levels may be protective against reactions.
      3. If an anaphylactoid reaction occurs, stop the infusion immediately and treat with diphenhydramine if urticaria, angioedema, or both are present and with epinephrine for more serious reactions (shock, bronchoconstriction). Once symptoms have resolved, the infusion may be recommenced at a slower rate (by further dilution and given over at least 1 hour).
    3. Note: Dilutional hyponatremia and seizures developed in a 3-year-old after IV administration from excess free water (see Item VI.C.2 below for precautions regarding pediatric dilution).
    4. Use in pregnancy. FDA Category B (see Table III-1). There is no evidence of teratogenicity. Use of this drug to treat acetaminophen overdose is considered beneficial to both mother and developing fetus. However, maternal hypotension or hypoxia due to a serious anaphylactoid reaction from IV administration may harm the fetus.
  5. Drug or laboratory interactions
    1. Activated charcoal adsorbs NAC and may interfere with its systemic absorption. When both are given orally together, data suggest that peak NAC levels are decreased by about 30% and that the time to reach peak level may be delayed. However, these effects are not considered clinically important.
    2. NAC can produce a false-positive test for ketones in the urine.
    3. NAC can prolong the measured prothrombin time (by 0.2-3.9 seconds) and INR.
  6. Dosage and method of administration. Acetylcysteine can be given orally or intravenously, although most clinicians use the intravenous formulation.
    1. Oral NAC. Use the inhaled mucolytic agent orally. Dilute with juice or soda, cover the container, and administer with a straw, to hide its characteristic sulfur odor and enhance palatability. Oral dilution guidelines are presented in Table III-2.
      1. Loading oral dose. Give 140 mg/kg of the 10% (1.4 mL/kg) or 20% (0.7 mL/kg) solution. Dilute the loading dose of 10% NAC with 1.4 mL/kg of juice or soda (for 20% NAC dilute with 2 mL/kg of juice/soda).
      2. Maintenance oral dose. Give 70 mg/kg (as a 5% solution) every 4 hours. Dilute the maintenance dose of 10% NAC (0.7 mL/kg) with 0.7 mL/kg of juice or soda (for 20% NAC, dilute 0.35 mL/kg with 1 mL/kg of juice/soda).
      3. Duration of oral treatment. The traditional protocol for treatment of acetaminophen poisoning in the United States called for 17 doses of oral NAC given over 72 hours. However, several studies have established the safety and efficacy of a shortened course of oral NAC. We recommend 70 mg/kg every 4 hours until acetaminophen is no longer detectable and hepatic aminotransferases have either remained in the normal range or if elevated, are down trending along with improvement in markers of synthetic function (eg, INR, bilirubin).
    2. Intravenous NAC is the preferred regimen if the patient is unable to tolerate the oral formulation (eg, vomiting, ileus, intestinal obstruction, other GI problems).
      1. Standard IV dosing. The manufacturer recommends the following 21-hour regimen for uncomplicated poisonings (see Table III-3): a loading dose of 150 mg/kg (maximum dose, 15 g) over 60 minutes, followed by 50 mg/kg (maximum 5 g) over 4 hours and then 100 mg/kg (maximum 10 g) over 16 hours.
      2. Duration of IV treatment. If there is evidence of hepatic toxicity or persistent measurable acetaminophen in the serum at the end of the 21-hour protocol, continue the 16-hour NAC maintenance infusion until acetaminophen is no longer detectable and hepatic aminotransferases have either remained in the normal range or, if elevated, are down trending along with improvement in markers of synthetic function (eg, INR, bilirubin).
      3. Massive ingestion. The standard IV dosing regimen may be inadequate for a patient with a very large acetaminophen overdose (eg, reported ingestion of more than 30 g or serum level greater than twice the nomogram line). In this case we recommend a modified 2-bag regimen consisting of the usual loading dose (150 mg/kg over 1 hour, maximum 15 g) followed by an infusion of 300 mg/kg over 20 hours (maximum 30 g), continuing the second infusion if acetaminophen remains detectable or there is evidence of hepatic toxicity, as described above (B.2.).
        1. Contact a medical toxicologist or poison center (1-800-222-1222) for advice in managing massive ingestions
        2. Note: Some clinicians are using the 2-bag regimen routinely instead of the standard 3-bag protocol, because of convenience and simplicity.
      4. Pediatric patients should have an alternate dilution volume or a saline-containing solution to avoid overhydration and hyponatremia (see Table III-3 for IV administration guidelines and precautions).
      5. Many patients can be switched to an oral regimen after the first one to two IV doses if vomiting has ceased.
      6. If intravenous NAC is not available, then the oral preparation may be administered by the IV route (with use of an in-line micropore filter). Contact a medical toxicologist or poison center (1-800-222-1222) for advice.
    3. Dosage during hemodialysis. The clearance of NAC may be doubled during hemodialysis. Increase the infusion rate during hemodialysis (eg, if receiving the 4-hour bag increase to 25 mg/kg/h or if receiving the 16-hour bag increase to 12.5 mg/kg/h), and administer an additional half loading dose of 75 mg/kg if hemodialysis exceeds 6 hours.
TABLE III-2. DILUTION GUIDELINES FOR ORAL ADMINISTRATION OF N-ACETYLCYSTEINE (NAC)
Volume of NAC (mL/kg)Approximate Volume of Soda/Juice Needed to Make 5% Solution (mL/kg)
Loading dose (140 mg/kg)
With 20% NAC (200 mg/mL) solution0.72
With 10% NAC (100 mg/mL) solution1.41.4
Maintenance dose (70 mg/kg)
With 20% NAC (200 mg/mL) solution0.351
With 10% NAC (100 mg/mL) solution0.70.7
TABLE III-3. DILUTION GUIDELINES FOR INTRAVENOUS ADMINISTRATION OF ACETYLCYSTEINE
Dose of Acetylcysteine (20% Solution = 200 mg/mL)Volume of Diluent (D5W)a NeededDuration of Infusion
Loading dose (150 mg/kg)0.75 mL/kgb

3 mL/kg (children <20 kg)

100 mL (children 20-40 kg)

200 mL (adults)

Over at least 45-60 minutes recommended to reduce risk for anaphylactoid reactions.
First maintenance dose (50 mg/kg)0.25 mL/kgb,c

7 mL/kg (children <20 kg)

250 mL (children 20-40 kg)

500 mL (adults)

Over 4 hours.
Second maintenance dose (100 mg/kg)0.5 mL/kgb,c

14 mL/kg (children <20 kg)

500 mL (children 20-40 kg)

1,000 mL (adults)

Over 16 hours. Repeat as needed (see text).

aManufacturer indicates that NAC is also stable in 0.45% normal saline at room temperature for 24 hours.

bManufacturer suggests the following for patients weighing more than 100 kg: loading dose = 15 g (75 mL); 4-hour maintenance dose = 5 g (25 mL); 16-hour maintenance dose = 10 g (50 mL).

c Larger doses of NAC may be needed after massive ingestions (see text).