N-acetyl cysteine administration
150 mg/kg IV over 1 hour
50 mg/kg IV over 4 hours
100 mg/kg IV over 16 hours
200 mg/kg IV over 4 hours
100 mg/kg IV over 16 hours
The US Food and Drug Administration (FDA) has determined that NAC is in pregnancy risk category B. (Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.)
An oral dosing regimen is also available; however, oral dosing tends to be reserved for those patients with anaphylactoid reactions and lasts 72 hours given the poor oral bioavailability of NAC due to high first pass metabolism.
140 mg/kg by mouth
70 mg/kg by mouth every 4 hours for 17 doses
All routes and strategies of NAC administration are equally as effective for acute acetaminophen (APAP) toxicity if performed correctly.
NAC may be used outside the standard 21-hour (IV) or 68-hour (oral) regimens, for instance in massive APAP overdose or delayed presentation after APAP overdose. Consultation with a toxicologist or local Poison Control Center (800-222-1222) is recommended in these circumstances.
Indications: NAC is primarily indicated and FDA-approved for treating APAP toxicity in the emergency department (ED). In the setting of an acute overdose with estimated time of ingestion, a 4-hour APAP level should be obtained. This ensures that any ingested drug has passed through its absorptive phase. The level should then be plotted against the Rumack-Matthew nomogram. If the level supersedes the treatment line, NAC antidotal therapy should be initiated ideally within 8-10 hours from ingestion.
In the setting of a patient with unknown time of ingestion and high clinical concern for APAP toxicity, a random APAP level should be obtained as soon as possible. In this setting, the mere presence of a detectable APAP level would indicate the need for antidotal therapy with NAC.
NAC can also be used as a supportive therapy for toxicants causing hepatocellular oxidative damage. For example, NAC may be beneficial in treating amatoxins (from Amanita and Lepiota spp, including the death cap mushroom), carbon tetrachloride, and ricin and may have a role in treating other toxins.
Contraindications: Given the volume of fluid required to dilute the NAC in both the 2- and 3-bag protocol, NAC should be used with caution in patients who are extremely volume sensitive (eg, severe heart failure with reduced ejection fraction); however, the hospital pharmacies usually can alter the diluent amount to improve patient tolerance.
There are no absolute contraindications for NAC administration.
Monitoring: No specific hematologic monitoring is required for NAC as a pharmacotherapy; however, it is recommended to obtain APAP levels, a complete metabolic panel, and coagulation studies in patients with acute or presumed acute APAP ingestions. Minimizing delays during the infusion process is paramount. For questions on specific monitoring in acute APAP ingestion, please contact your local toxicologist or poison control center in the United States at 800-222-1222.
It is important to note that NAC interferes with the prothrombin time / international normalized ratio (PT/INR) assay in vitro, and coagulation studies drawn after the initiation of antidotal therapy may be spuriously prolonged. NAC alone should not prolong the INR beyond 1.3.
Adverse effects: IV NAC can cause anaphylactoid reactions in approximately 10% of patients. The literature indicates a slight, nonstatistically significant trend of anaphylactoid reactions in the 3-bag system and suggests the high loading dose may be to blame. Severe reactions with resultant bronchospasms are rare; patients with asthma tend to be at higher risk. Patients with lower APAP levels have a higher propensity to anaphylactoid reactions as APAP blocks histamine release from mast cells and monocytes in a dose-dependent manner.
Oral NAC has a high rate of nausea, vomiting, diarrhea, and gastrointestinal upset, often making it difficult to tolerate the 3-day oral regimen. Nonacetaminophen analgesia and antiemetics are mainstays of treatment.
If anaphylactoid reaction occurs, pause the infusion and treat the patient with antihistamines and crystalloids (if necessary for hypotension). The infusion can be restarted at a slower rate once symptoms have improved. For persistent anaphylactoid reactions, consider switching to the oral regimen.
Toxicity: NAC is generally considered an extremely safe drug, and toxicity does not stem from therapeutic doses. Several case studies have shown severe toxicity from iatrogenic dosing errors where delivered doses were tenfold higher than intended. Reports of NAC overdose include acute renal failure and acidosis, hemolysis, hemolytic uremic syndrome, and seizures. Cerebral edema, permanent brain injury, and death have also been reported, but these are exceedingly rare.
Mechanism of action: NAC is used to regenerate liver glutathione (GSH) stores to combat the oxidative free radical damage caused by the toxic byproduct of APAP overdose. Although most APAP is metabolized by glucuronidation or sulfation, about 5% of APAP is shuttled through the CYP450 system. CYP2E1 unfortunately creates a toxic byproduct, N-acetyl-p-benzoquinone imine (NAPQI), which damages hepatocytes. This molecule, which is an oxidative free radical, then leads to upregulation of cell death proteins, dissolution of electron transport chain proteins, and metabolic damage, in addition to the free radical damage. NAC directly detoxifies NAPQI and allows priming and regeneration of glutathione, an antioxidant system.
As mentioned above, NAC can be used for numerous other toxicants that cause hepatocellular damage. When used for these purposes, the primary benefit is providing the liver with an added ability to combat oxidative damage and scavenge free radicals.