Treatment of acetaminophen poisoning consists primarily of the timely use of the antidote acetylcysteine and supportive care.1,36,37 For most cases of acetaminophen poisoning, adequate GI decontamination consists of the early administration of activated charcoal orally or through a nasogastric tube.1,43,44 Inducing emesis by administering ipecac syrup is undesirable because it delays the administration of the oral antidote. In addition, more aggressive forms of decontamination, such as gastric lavage or whole-bowel irrigation, are unnecessary because of the rapid GI absorption of acetaminophen and the great success of treating acetaminophen poisoning with acetylcysteine.
The mainstay for the prevention or treatment of acetaminophen toxicity is the administration of acetylcysteine.1,45,46,47 The current "standard" acetylcysteine protocols were developed from primarily observational trials, and it is not clear if they represent the most effective regimens.48
Although its mechanisms of action are not fully understood, acetylcysteine is thought to have two important beneficial effects.47,48 In early acetaminophen poisoning (<8 hours after ingestion), acetylcysteine averts toxicity by preventing the binding of NAPQI to hepatic macromolecules. Acetylcysteine may do this by acting as a glutathione precursor or substitute, or a sulfate precursor, or it may directly reduce NAPQI back to acetaminophen. In established acetaminophen toxicity or >24 hours after acetaminophen ingestion, acetylcysteine diminishes hepatic necrosis by acting as an antioxidant, decreasing neutrophil infiltration, improving microcirculatory blood flow, or increasing tissue oxygen delivery and extraction.
If acetylcysteine is given within 8 hours of an acute acetaminophen ingestion, it is nearly 100% effective in preventing the development of hepatotoxicity.39 The longer the initiation of acetylcysteine therapy is delayed beyond 8 hours after ingestion, the greater the risk of developing hepatotoxicity.49 Even up to 24 hours following acetaminophen ingestion, however, acetylcysteine treatment is associated with a lower risk of hepatotoxicity than historical controls.39
Clinical experience suggests that patients with poor glutathione reserves, such as alcoholics and the chronically ill, have similar excellent clinical outcomes when the standard treatment guidelines are applied to their care. As such, there is no need to alter the use of the acetaminophen treatment nomogram or modify the dosing of acetylcysteine for these patients.
The weight of evidence suggests that acetylcysteine therapy is both safe and efficacious during pregnancy and that the approach to treating a pregnant patient following an acetaminophen overdose should remain the same. Although an ovine model demonstrated that acetylcysteine is unable to cross the placenta, there are data in humans establishing that it does.50 Acetylcysteine treatment has never been associated with fetal malformations in humans, but fetal demise and malformations have been described following delayed acetylcysteine treatment after acetaminophen overdose in first-trimester pregnant women.51
IV acetylcysteine has been used to supplant oral administration due to its greater ease of administration, greater patient acceptance, equivalent efficacy, and shorter duration of treatment for many cases of acetaminophen poisoning.52,53,54,55 The major limitation of IV acetylcysteine is the occurrence of drug-related anaphylactoid reactions (occurring during the first 2 hours of administration), which in mild cases is treated with diphenhydramine and in severe cases is treated by temporarily slowing/stopping the acetylcysteine infusion.56 The risk of anaphylactoid reaction from IV acetylcysteine ranges from 4% to 17%.57,58,59,60 Asthmatics appear to have a greater risk of anaphylactoid reactions during IV acetylcysteine therapy, whereas overdose patients with high acetaminophen concentrations appear to have a lower risk of developing anaphylactoid reactions.59,60,61,62 Approximately 13% of patients treated with IV acetylcysteine develop nausea and vomiting.63 Rare complications, including status epilepticus, hemolytic uremic syndrome, cerebral edema, and death, have been reported following massive overdose of IV acetylcysteine.64,65,66,67
The standard regimen for IV acetylcysteine utilizes a 20-hour protocol with a loading dose of 150 milligrams/kg over 15 minutes to 1 hour, followed by a first maintenance dose of 50 milligrams/kg infused over 4 hours, and then followed by a second maintenance dose of 100 milligrams/kg infused over 16 hours (Table 190-2). Administering the initial dose over an hour appears to minimize the incidence of drug-related adverse effects, particularly anaphylactoid responses, although this belief has not been substantiated when prospectively studied.58 Because the three-phase dosing regimen for IV acetylcysteine may result in dosing errors and produce side effects due to the initial high infusion rate, alternative dosing regimens are being explored.68,69,70
TABLE 190-2Acetylcysteine Dosing Regimens ||Download (.pdf) TABLE 190-2 Acetylcysteine Dosing Regimens
| ||Oral ||IV Adult ||IV Pediatric (<40 kg) |
|Preparation || |
Available as 10% and 20% solutions.
Dilute to 5% solution for oral administration.
|Available as 20% solution. || |
Available as 20% solution.
Dilute to 2% solution by mixing 50 mL in 450 mL 5% dextrose in water.
|Loading dose ||140 milligrams/kg. ||150 milligrams/kg in 200 mL 5% dextrose in water infused over 15–60 min. ||150 milligrams/kg (7.5 mL/kg) infused over 15–60 min. |
|Maintenance dose ||70 milligrams/kg every 4 h for 17 doses. || |
50 milligrams/kg in 500 mL 5% dextrose in water infused over 4 h (12.5 milligrams/kg per hour).
100 milligrams/kg in 1000 mL 5% dextrose in water infused over 16 h (6.25 milligrams/kg per hour).
50 milligrams/kg (2.5 mL/kg) infused over 4 h (12.5 milligrams/kg per hour).
100 milligrams/kg (5 mL/kg) infused over 16 h (6.25 milligrams/kg per hour).
|Duration of therapy ||72 h. ||20 h. ||20 h. |
|Comments || |
Dilute with powdered drink mix, juice, or soda.
Drink through a straw to reduce disagreeable smell.
|Monitor for drug-related adverse effects and anaphylactoid reactions. || |
Monitor for drug-related adverse effects and anaphylactoid reactions.
500 mL of the 2% solution prepared as described above is enough to treat a 33-kg child for the full 20-h course.
IV acetylcysteine is commercially available as a 20% solution and requires dilution to a 2% solution for infusion into a peripheral vein. Both 5% dextrose in water and half-normal saline can be used as diluents.71 Given the volume and hypotonicity of fluid required, children and small adults should be carefully monitored to avoid fluid overload and hyponatremia during treatment.52
Despite the lack of randomized direct comparisons, IV acetylcysteine is as effective and safe as oral therapy for patients with early acetaminophen poisoning, as compared with retrospective cohorts and historical controls.54,72,73,74,75 IV acetylcysteine is the route of choice for patients with acetaminophen-induced fulminant hepatic failure, because oral acetylcysteine has not been adequately studied in this setting.76 There is the potential for delayed hepatic toxicity after the completion of acetylcysteine therapy, especially the 20-hour IV protocol.77
The standard 72-hour oral acetylcysteine regimen used in the United States consists of a loading dose of 140 milligrams/kg followed by maintenance doses of 70 milligrams/kg every 4 hours for 17 additional doses (Table 190-2). It may still be appropriate in certain patients, such as those at high risk for anaphylactoid responses to the IV formulation and asthmatics. The taste is disagreeable, and some patients with persistent nausea and vomiting may require concomitant antiemetics such as ondansetron.
Case reports describe the use of extracorporeal detoxification in patients presenting late after a serious acetaminophen overdose to both remove the drug and treat the hepatic encephalopathy.78,79 The role of such therapy in the overall management of serious acetaminophen toxicity remains to be defined.
TREATMENT GUIDELINES BASED ON TIME TO ED PRESENTATION
Treatment guidelines for oral acetaminophen poisoning are based on the time to presentation to the ED after ingestion: <4 hours, between 4 hours and 24 hours, and unknown time or >24 hours before presentation (Figure 190-3).37 In toxic overdoses, the risk of hepatotoxicity increases with the lag time between ingestion and initiation of acetylcysteine therapy.49 The optimal outcome with acetylcysteine therapy is seen if it is administered within 8 hours after ingestion, so the optimal "decision-time window" for treatment is between the 4-hour acetaminophen concentration measurement and 8-hour goal to initiate acetylcysteine.39 No further acetaminophen serum measurements are necessary once the need for acetylcysteine therapy has been determined until the completion of the course of therapy.
Treatment guidelines for acetaminophen (APAP) ingestion. All times noted are postingestion. AC = acetylcysteine; ALT = alanine aminotransferase; AMS = altered mental status; AST = aspartate aminotransferase; Cr = creatinine; LFTs = liver function tests; PT = prothrombin time; Rx = treatment.
Presentation Within 4 Hours of Ingestion
For patients who present to the ED within 4 hours and are likely have a significant acetaminophen overdose, treatment begins with GI decontamination (usually activated charcoal) while awaiting the 4-hour postingestion acetaminophen concentration. If the clinical laboratory can report an acetaminophen concentration within 8 hours postingestion, wait for the serum acetaminophen concentration and plot the result on the nomogram to determine whether acetylcysteine therapy is necessary. If the acetaminophen concentration will not be available by 8 hours postingestion, empirically initiate acetylcysteine therapy without waiting for the result. Subsequently, when the acetaminophen concentration is determined, the need for acetylcysteine therapy can be determined with the use of the nomogram.
Presentation >4 and <24 Hours After Ingestion
For patients who present >4 hours but <24 hours following acetaminophen ingestion, determine the serum acetaminophen concentration as soon as possible. GI decontamination may be performed, particularly for suspected coingestants, but it may have limited effectiveness because of the delay in presentation. If the laboratory can determine the acetaminophen concentration within 8 hours postingestion, await the acetaminophen concentration and plot the result on the nomogram to determine if acetylcysteine therapy is necessary. Otherwise, empirically administer acetylcysteine.
Presentation >24 Hours After Ingestion or Time of Ingestion Unknown
For patients in whom the time of acetaminophen ingestion remains unknown or is >24 hours or for those with suggestive clinical findings of acetaminophen poisoning, a serum acetaminophen concentration and serum transaminase, bilirubin, and prothrombin time tests should be determined. Initiate acetylcysteine therapy as soon as possible while awaiting laboratory results. In this scenario, a detecTable acetaminophen concentration (>10 micrograms/mL or >66 micromoles/L) suggests that the patient may be at risk for developing hepatotoxicity. Similarly, elevated serum transaminases suggest the possibility of ongoing hepatic toxicity. Therefore, continued acetylcysteine therapy is indicated if the acetaminophen concentration is measurable or if the serum transaminases are elevated. If serum acetaminophen concentration is <10 micrograms/mL (<66 micromoles/L) and the serum transaminases are not elevated, then acetylcysteine can be discontinued.