Acetaminophen poisoning has had the Food and Drug Administration on alert for several years. More than 200 million people consume acetaminophen each year, and about 200 of these die due to hepatic failure associated with acetaminophen toxicity.1,2
In 2009, acetaminophen was the most common reason for phone calls to poison control centers. It contributed to approximately 20% of deaths caused by toxic pharmaceutical exposures when used alone or in combination with other medications.3 In 2010, more than 16.5% of deaths caused by toxic pharmaceutical exposures were associated with acetaminophen.4
Healthcare providers must be aware of current literature and evidence-based management strategies to ensure optimal delivery of medical treatment for acetaminophen toxicity.
Patients experiencing acetaminophen toxicity often exhibit few physical examination findings. Providers therefore must be able to quickly identify and prioritize actual and potential problems, order appropriate diagnostic procedures and implement necessary interventions.
To increase the likelihood of proper treatment and monitoring for acetaminophen toxicity, standardized order sets should be used. Standardized order sets increase patient safety and improve outcomes by assuring delivery of consistent evidence-based treatment, appropriate monitoring and reduced medication errors.5,6 By using these sets, providers are able to complete more comprehensive orders and ancillary staff members are able to better understand these orders based on familiarity and consistency.
Acetaminophen Toxicity
Acetaminophen is a nonopioid analgesic commonly used to treat minor aches and pains. It is available as a single-ingredient product or in combination products; a few preparations are available only with a prescription. The drug works as a weak COX-1 and COX-2 inhibitor in peripheral tissues and has antipyretic properties.7
In therapeutic doses, about 90% of acetaminophen is conjugated in the liver to nontoxic metabolites. Another small portion forms the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Toxicity occurs when the usual metabolic pathways are overwhelmed. When a large amount of acetaminophen is ingested, NAPQI accumulates and cellular injury of the liver occurs. Medical treatment is usually required if ingestion is greater than 10 g or 200 mg/kg (whichever is less) over a 24-hour period.8
Early symptoms of acetaminophen overdose or toxicity are not always evident. Some patients who present within 24 hours after acetaminophen overdose may display or report nausea, vomiting, diaphoresis, pallor, malaise and lethargy.8,9 After the initial 24 hours, patients may develop abdominal pain and hypotension if toxicity is significant. If toxicity is severe, hepatic encephalopathy, cerebral edema, hypoglycemia, coagulopathy and jaundice can occur.8-10
A serum acetaminophen level should be obtained upon first suspicion of toxicity.11 Older studies report no correlation between the amount of drug ingested and serum concentration, but more recent studies have found that serum concentration can be a reliable source to determine the amounts of acetaminophen ingested.12,13 It is most beneficial to obtain this serum level 4 to 6 hours after ingestion, which is when acetaminophen levels peak.
The Rumack-Matthew nomogram14 is a tool used to assess the likelihood of hepatotoxicity using serum concentrations taken approximately 4 to 6 hours after ingestion and 16 to 24 hours after ingestion.15 Patients with a history of long-term acetaminophen use, repeated ingestion or use of extended-release formulations may not be good candidates for the Rumack-Matthew nomogram. If toxicity is suspected but serum values are questionable, N-acetylcysteine (NAC) should be administered.8,12
Review of Treatment
If acetaminophen overdose is significant charcoal can prevent its absorption.11,16,17 However, the benefits and risks of this treatment must be evaluated. NAC is the antidote of choice, and in cases of delayed treatment, resuscitation efforts may be required.10,11,19
Acetaminophen toxicity can range from mild to severe. Mild cases may only need monitoring of laboratory values, while patients who have a late presentation to healthcare intervention may have significant liver injury. Severe toxicity can result in encephalopathy, hypoglycemia, coagulopathy, hypotension and death from fulminant hepatic failure.10 Support for extreme toxic cases may result in resuscitation with intubation, fluids, vasopressors, dextrose and fresh frozen plasma.10
Activated charcoal has been used for years to treat the ingestion of toxic substances. It absorbs and binds to toxic substances and allows the substance to transfer out of the body.17,20,21 Charcoal has been used frequently in the treatment of acetaminophen overdoses. Adults, adolescents and children who present in a short period of time after acetaminophen ingestion may benefit from activated charcoal.
When it is given less than 2 hours after initial ingestion, charcoal can reduce the 4-hour peak level of serum acetaminophen and consequently decrease hepatotoxicity, length of hospital stay and perhaps reduce the need for treatment with NAC.11,16,17
The benefits of activated charcoal should be weighed against the possible risks associated with its administration. The most significant of these effects is aspiration pneumonitis, which can be fatal.18
NAC has been used since the early 1970s as an antidote to acetaminophen toxicity. NAC has hepatoprotective properties. It restores sulfhydryl donors and glutathione, which aid in acetaminophen metabolism, thereby limiting creation of toxic metabolites.
Two routes have been proven effective when administering NAC. Oral and intravenous (IV) administration of this drug has comparable outcomes. However, oral dosing has more adverse effects, such as nausea and vomiting. Due to the increased risk of emesis, subtherapeutic levels in treatment are likely and intravenous dosing may be favorable.22
By using the Rumack-Matthew nomogram, the level of risk for probable hepatotoxicity can be assessed to guide use of NAC.14,23,24
This tool has proven useful in acute ingestion when the time of ingestion is known. Patients treated with NAC within 8 hours face little to no risk of hepatotoxicity.
The risk of liver injury more than doubles when overdose is not treated for 10 or more hours after ingestion. If NAC treatment is not initiated until 16 to 24 hours after ingestion, liver injury is expected.23,24
Outcomes are better when NAC is initiated within 8 hours of suspected acetaminophen ingestion. The incidence of hepatotoxicity appears to increase after 8 to 10 hours.23,24
Treatment with NAC should be given to any initial serum value reported as above the possible hepatotoxicity line on the nomogram.
The guidelines for IV administration of NAC recommend sequential infusions lasting just more than 20 hours.
In adult patients weighing more than 40 kg, the loading dose is 150 mg/kg in 200 mL of 5% dextrose in water (D5W) infused over 60 minutes, followed by a 50 mg/kg dose in 500 mL of D5W over 4 hours. The last infusion is 100 mg/kg in 1,000 mL of D5W infused over 16 hours.9,20
In patients weighing 20 kg to 40 kg, the loading dose is 150 mg/kg in 100 mL of 5% D5W infused over 60 minutes, followed by 50 mg/kg in 250 mL of solution infused over 4 hours, followed by 100 mg/kg in 500 mL infused over 16 hours.
In patients weighing less than 20 kg, the loading dose is 150 mg/kg in 3 mL/kg of D5W infused over 60 minutes, followed by 50 mg/kg in 7 mL/kg solution over 4 hours, and completed with 100 mg/kg in 14 mL/kg of solution infused over 16 hours.26
Oral dosing of acetylcysteine consists of a loading dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for a total of 17 doses.11,26 This need for frequent dosing may result in late, incomplete or missed doses.
Adherence may be compromised with the oral dosing method because total doses extend to 72 hours of treatment. If complications occur with oral dosing, the administration route should be changed to IV, which may cost more but could ensure sufficient dosing.11
Monitoring
Acetaminophen levels should be trended and treated according to toxicity level. Electrolytes, liver enzymes, bilirubin and coagulation should be observed. The liver enzymes alanine transaminase and aspartate transaminase can elevate but should peak within 96 hours.
Bilirubin and coagulation values such as prothrombin time and international normalized ratio should be carefully monitored because these are the most specific for liver dysfunction.
Acute tubular necrosis may occur and manifest as increased creatinine and blood urea nitrogen.10,15 Mentation should be observed carefully for acute changes.
Why Standardize?
Medical errors in the United States cause thousands of preventable deaths each year and cost the healthcare system billions of dollars.27 Most medical errors result from drug complications such as medication errors.
In hospital settings, the rate of adverse drug events ranges from 2 to 7 per 100 admissions, and about one-third of these events are associated with preventable medication errors.28 Standardized order sets decrease medication errors, costs, length of hospitalization and overall mortality.5,6
A standardized order set is a comprehensive clinical decision support tool used by healthcare providers when entering orders for patients. An order set can be customized to any diagnosis, surgical intervention or procedure and should be implemented based on the benefits it provides.
The use of standardized order sets is crucial when treating patients with acetaminophen toxicity. Medication errors involving NAC treatment for acetaminophen toxicity are as high as 33%.25
Errors most commonly involved include unnecessary antidotal therapy, no therapy despite indication, incorrect infusion rates, and interruptions in continuous therapy.
Incorrect dosing, such as oral doses given intravenously, has also been reported.25
Several factors affect the management of acetaminophen toxicity and can be improved with the use of standardized order sets.
First, accurate determination of necessary treatment should be included to assist providers in implementing therapy. The time of ingestion in coordination with the timing and value of the serum acetaminophen level should be taken into consideration when evaluating treatment. The use of predetermined instructions regarding charcoal administration allows it be delivered within the timeline that evidence-based studies suggest.
Order sets can be used to guide treatment based on acetaminophen values and the Rumack-Matthew nomogram. Utilization of the nomogram can increase proper initiation of evidence-based treatment as well as prompt follow-up on serum acetaminophen levels to evaluate toxicity risk.
In addition, a standardized evidence-based medication regimen that is clearly depicted for ancillary staff can greatly decrease medication errors, especially with NAC dosing.
Oral management is challenging because of frequency, length of time for therapy and adverse events causing subtherapeutic dosing.11 The IV regimen is complex because it involves three different concentrations delivered over various time frames.
To further complicate the management with intravenous NAC, several different providers must administer the drug because of the length of time required for therapy. If at all possible, the infusion should not be interrupted.
Preventable errors have decreased with the implementation of standardized order sets.5,6,29
Formatted medications with correct dosing, route and frequency ensure that medication orders have all necessary components.
The Institute of Medicine recommends implementing computerized provider order entry and/or standardizing prescription writing to assist in decreasing medication errors.30
The agency has published guidelines for this so that improved patient safety can be achieved.30
Find a copy of the Institute for Safe Medication Practices' guide for standard order sets atwww.ismp.org/tools/guidelines/standardordersets.pdf.
References
1. Park A. The FDA's painkiller warning: how to avoid taking too much. http://www.time.com/time/health/article/0,8599,1572012,00.html
2. Rowden A, et al. Acetaminophen poisoning. Clin Lab Med. 2006;26(1):49-65.
3. Bronstein A, et al. 2009 annual report of the American Association of Poison Control Centers' National poison data system (NPDS): 27th annual report. Clin Toxicol. 2010; 48(10):979-1178.
4. Bronstein A, et al. 2010 annual report of the American Association of Poison Contol Centers' National poison data system (NPDS): 28th annual report. Clin Toxicol. 2011;49(10):910-941.
5. Fishbane S, et al. The impact of standardized order sets and intensive clinical case management on outcomes in community-acquired pneumonia. Arch Intern Med. 2007;167(15):1664-1669.
6. Ballard DJ, et al. The impact of standardized order sets on quality and financial outcomes. In: Advances in Patient Safety: New Directions and Alternative Approaches. Rockville, Md.: Agency for Healthcare Policy and Research; 2008: 1-15.
7. Furst DE, et al. Nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic agents nonopioid analgesics drugs and drugs used in gout. In: Katzung BG, et al. Basic and Clinical Pharmacology. 11th ed. New York, NY; McGraw-Hill; 2009: 635-636.
8. Dart RC, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2006;44(1):1-18.
9. Alapat PM, Zimmerman JL. Toxicology in the critical care unit. Chest. 2008;133(4):1006-1013.
10. Polson J, Lee WM. AASLD position paper: The management of acute liver failure. Hepatology. 2005;41(5):1179-1197.
11. Temple A, Baggish J. Guidelines for the management of acetaminophen overdose. McNeil Consumer & Specialty Pharmaceuticals. http://www.tylenolprofessional.com/assets/Overdose_Monograph.pdf%20
12. Read RB, et al. Analysis of factors responsible for continuing mortality after paracetamol overdose. Hum Toxicol. 1986;5(3):201-206.
13. Zyoud S, et al. Reliability of the reported ingested dose of acetaminophen for predicting the risk of toxicity in acetaminophen overdose patients. Pharmacoepidemiol Drug Saf. 2012;21(2):207-213.
14. The Merck Manual. The Rumack-Matthew nomogram for single acute acetaminophen poisoning. http://www.merckmanuals.com/professional/injuries_poisoning/poisoning/acetaminophen_poisoning.html#v1118635%20
15. Wolf SJ, et al. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med. 2007;50(3):292-313.
16. Buckley NA, et al. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol. 1999;37(6):753-757.
17. Christophersen AB, et al. Activated charcoal alone or after gastric lavage: a simulated large paracetamol intoxication. Brit J Clin Pharmacol. 2002;53(3):312-317.
18. Isbister G, Kumar K. Indications for single-dose activated charcoal administration in acute overdose. Curr Opin Crit Care. 2011;17(4):351-357.
19. Koulouris Z, et al. Metabolic acidosis and coma following a severe acetaminophen overdose. Ann Pharmacother. 1999;33(11):1191-1194.
20. Heard K. Gastrointestinal decontamination. Med Clin N Am. 2005;89(6):1067-1078.
21. Olson KR. Management of the poisoned patient. In: Katzung BG, et al. Basic and Clinical Pharmacology. 11th ed. New York, NY; McGraw-Hill; 2009: 17.
22. Bebarta VS, et al. A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose. Clin Toxicol. 2010;48(5):424-430.
23. Prescott LF. Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. Arch Intern Med. 1981;141(3):386-389.
24. Rumack B, et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141(3):380-385.
25. Hayes B, et al. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother. 2008;42(6):766-770.
26. Acetadote (Acetylcysteine). mobileMicromedex. Thomson Reuters Inc; Version 5.1, 2012.
27. Institute of Medicine. To err is human: Building a safer health system. http://www.iom.edu/%7E/media/Files/Report%20Files/1999/To-Err-is-Human/To%20Err%20is%20Human%201999%20%20report%20brief.pdf
28. Kaushal R, Bates DW. Information technology and medication safety: what is the benefit? Qual Saf Health Care. 2002;11(3):261-265.
29. Micek ST, et al. Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med. 2006;34(11):2707-2713.
30. Institute for Safe Medication Practices. ISMP develops guidelines for standard order sets. http://http://www.ismp.org/newsletters/acutecare/articles/20100311.asp