How does acetaminophen toxicity occur. What are the symptoms of acetaminophen poisoning. How is acetaminophen overdose treated. When should you seek medical attention for acetaminophen toxicity. What are the long-term effects of acetaminophen overdose. How can acetaminophen toxicity be prevented. Are there alternatives to acetaminophen for pain relief.

Understanding Acetaminophen and Its Toxic Potential

Acetaminophen, also known as paracetamol, is a widely used over-the-counter pain reliever and fever reducer. While it’s generally safe when taken as directed, acetaminophen can be toxic in large doses. Understanding the risks associated with this common medication is crucial for preventing accidental overdoses and potential liver damage.

What is acetaminophen?

Acetaminophen is an analgesic (pain reliever) and antipyretic (fever reducer) found in numerous medications, including Tylenol and many combination cold and flu products. It works by inhibiting the production of prostaglandins, substances in the body that cause inflammation and pain.

How does acetaminophen toxicity occur?

Acetaminophen toxicity typically occurs when a person takes more than the recommended dose, either intentionally or accidentally. This can happen by:

• Taking multiple doses too close together
• Using multiple products containing acetaminophen without realizing it
• Consuming alcohol while taking acetaminophen
• Taking acetaminophen with certain other medications that affect liver function

The liver metabolizes acetaminophen, and when taken in excessive amounts, it can overwhelm the liver’s ability to process the drug safely, leading to liver damage.

Recognizing the Symptoms of Acetaminophen Toxicity

Identifying acetaminophen toxicity early is crucial for effective treatment. The symptoms can be subtle at first and may not appear immediately after ingestion.

Early symptoms of acetaminophen poisoning

Initial symptoms of acetaminophen toxicity may include:

• Nausea and vomiting
• Loss of appetite
• Abdominal pain, particularly in the upper right quadrant
• Fatigue or weakness
• Excessive sweating

Later symptoms indicating liver damage

As liver damage progresses, more severe symptoms may develop:

• Yellowing of the skin and eyes (jaundice)
• Confusion or disorientation
• Dark urine
• Pale stools
• Severe abdominal pain
• Bruising or bleeding easily

Is it possible to have acetaminophen toxicity without noticeable symptoms? Yes, in some cases, individuals may not experience obvious symptoms until significant liver damage has occurred. This is why it’s crucial to seek medical attention if you suspect an overdose, even if you feel fine.

Diagnosing Acetaminophen Toxicity

Prompt diagnosis is essential for effective treatment of acetaminophen toxicity. Healthcare providers use a combination of methods to assess the severity of the overdose and potential liver damage.

Blood tests for acetaminophen levels

The primary diagnostic tool for acetaminophen toxicity is a blood test that measures the concentration of acetaminophen in the blood. This test is most accurate when performed 4 to 24 hours after ingestion. The results are plotted on a nomogram, which helps predict the risk of liver toxicity based on the time since ingestion and the blood acetaminophen level.

Liver function tests

Additional blood tests are used to assess liver function and detect any signs of liver damage. These may include:

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels
• Bilirubin levels
• Prothrombin time (PT) to assess blood clotting function

Imaging studies

In some cases, imaging studies such as ultrasound or CT scans may be used to visualize the liver and assess for any signs of damage or inflammation.

Treatment Options for Acetaminophen Toxicity

The treatment for acetaminophen toxicity depends on the severity of the overdose and how quickly medical attention is sought. Prompt treatment is crucial for preventing or minimizing liver damage.

N-acetylcysteine (NAC) therapy

The primary treatment for acetaminophen toxicity is N-acetylcysteine (NAC), an antidote that helps protect the liver from damage. NAC works by replenishing glutathione, a substance in the liver that helps detoxify acetaminophen. How is NAC administered? NAC can be given orally or intravenously, depending on the severity of the overdose and the patient’s condition. Treatment typically continues for 20 to 72 hours, based on the patient’s response and liver function tests.

Activated charcoal

If the patient presents within 4 hours of ingestion, activated charcoal may be administered to help absorb any remaining acetaminophen in the stomach and prevent further absorption.

Supportive care

In addition to NAC therapy, supportive care measures may include:

• Intravenous fluids to maintain hydration
• Antiemetics to control nausea and vomiting
• Monitoring of vital signs and liver function
• Management of complications such as bleeding or encephalopathy

Liver transplantation

In severe cases where liver failure occurs despite treatment, liver transplantation may be necessary. This is typically considered a last resort when other treatments have failed and liver function continues to deteriorate.

Long-Term Effects and Prognosis of Acetaminophen Toxicity

The long-term effects of acetaminophen toxicity can vary widely depending on the severity of the overdose and how quickly treatment is initiated. Understanding the potential consequences is crucial for both patients and healthcare providers.

Liver damage and recovery

In cases where treatment is started early, complete recovery of liver function is possible. However, severe overdoses or delayed treatment can lead to permanent liver damage. Can the liver regenerate after acetaminophen toxicity? The liver has a remarkable ability to regenerate, and in many cases, patients can recover full liver function over time. However, this process can take weeks to months, and some patients may experience long-term liver problems.

Potential complications

Severe acetaminophen toxicity can lead to various complications, including:

• Acute liver failure
• Kidney damage
• Brain swelling (hepatic encephalopathy)
• Bleeding disorders
• Increased susceptibility to infections

Long-term monitoring

Patients who have experienced acetaminophen toxicity may require long-term monitoring of liver function and should be cautious about future use of acetaminophen and other potentially hepatotoxic substances.

Preventing Acetaminophen Toxicity

Prevention is key when it comes to acetaminophen toxicity. By understanding the risks and taking proper precautions, most cases of acetaminophen overdose can be avoided.

Safe dosing guidelines

Always follow the recommended dosing instructions on the medication label or as directed by your healthcare provider. The maximum daily dose for adults is typically 4,000 mg, but this may be lower for certain individuals or in specific circumstances.

Avoiding multiple acetaminophen-containing products

Be aware that many over-the-counter and prescription medications contain acetaminophen. Always check the active ingredients in all medications you’re taking to avoid accidentally exceeding the maximum daily dose.

Proper storage and child safety

Store all medications, including acetaminophen, in a secure location out of reach of children. Use child-resistant packaging and never refer to medication as “candy” to encourage children to take it.

Alcohol considerations

Limit alcohol consumption when taking acetaminophen, as alcohol can increase the risk of liver damage. If you have a history of alcohol abuse or liver disease, consult your healthcare provider before using acetaminophen.

Alternatives to Acetaminophen for Pain Relief

While acetaminophen is an effective pain reliever for many people, there are alternatives available for those who need to avoid it or are looking for different options.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs such as ibuprofen and naproxen can be effective alternatives to acetaminophen for pain relief and fever reduction. However, these medications come with their own set of risks and side effects, particularly for those with stomach ulcers, kidney problems, or a history of bleeding disorders.

Non-pharmacological pain management techniques

Several non-drug approaches can help manage pain, including:

• Physical therapy and exercise
• Heat or cold therapy
• Massage
• Acupuncture
• Meditation and relaxation techniques

Prescription pain medications

For more severe pain, prescription medications may be necessary. These should always be used under the guidance of a healthcare provider and with careful consideration of potential risks and side effects.

Are there natural alternatives to acetaminophen? Some people find relief from pain using natural remedies such as turmeric, ginger, or willow bark. However, it’s important to note that “natural” doesn’t always mean safe, and these alternatives can still interact with other medications or have side effects. Always consult with a healthcare provider before using any new pain management approach.

When to Seek Medical Attention for Suspected Acetaminophen Toxicity

Knowing when to seek medical help is crucial in cases of suspected acetaminophen overdose. Early intervention can significantly improve outcomes and prevent severe liver damage.

Immediate action for known overdose

If you know or suspect that you or someone else has taken more than the recommended dose of acetaminophen, seek medical attention immediately. Don’t wait for symptoms to appear, as liver damage can occur before visible signs of toxicity manifest.

Recognizing signs of potential toxicity

Even if you’re unsure about an overdose, be alert for signs that could indicate acetaminophen toxicity:

• Persistent nausea or vomiting
• Abdominal pain, especially in the upper right area
• Yellowing of the skin or eyes
• Confusion or unusual tiredness
• Dark urine or pale stools

Contacting Poison Control

In the United States, you can contact Poison Control at 1-800-222-1222 for immediate guidance on what to do in case of suspected acetaminophen overdose. They can provide expert advice on whether you need to seek emergency care or can be managed at home.

How quickly should you seek medical attention after a suspected overdose? It’s best to seek medical attention as soon as possible after a suspected overdose. The antidote for acetaminophen toxicity (N-acetylcysteine) is most effective when given within 8 hours of ingestion, but can still be beneficial up to 24 hours or more after the overdose.

Remember, acetaminophen is a safe and effective medication when used as directed. However, understanding its potential for toxicity and knowing how to recognize and respond to an overdose can save lives. Always use medications responsibly and seek medical advice if you have any concerns about their use or potential side effects.

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Electronic cigarettes (e-Cigs) are devices made to look like real cigarettes. They contain a battery, a heater, and liquid nicotine. When heated, the nicotine liquid becomes a vapor, which users inhale. Liquid nicotine products contain flavorings and something to help the product vaporize. Liquid nicotine products are very poisonous if swallowed.

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Acetaminophen Toxicity – StatPearls – NCBI Bookshelf

Continuing Education Activity

Acetaminophen toxicity is the second most common cause of liver transplantation worldwide and the most common cause of liver transplantation in the US. It is responsible for 56,000 emergency department visits, 2,600 hospitalizations, and 500 deaths per year in the United States. Fifty percent of these are unintentional overdoses. More than 60 million Americans consume acetaminophen on a weekly basis, and many are unaware that it is contained in combined products. This activity reviews the etiology, evaluation, and treatment of acetaminophen overdose and highlights the importance of the interprofessional team in both managing and preventing this problem.

Objectives:

• Review the pathophysiology of acetaminophen toxicity.

• Describe the four clinical stages of acetaminophen toxicity.

• Identify the treatment strategies for an alert patient who presents within an hour of overdose versus a patient who presents after two hours.

• Explain interprofessional team strategies for educating patients about acetaminophen toxicity with the goal of preventing overdose.

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Introduction

Acetaminophen (N-acetyl-para-aminophenol, paracetamol, APAP) toxicity is common primarily because the medication is so readily available, and there is a perception that it is very safe. More than 60 million Americans consume acetaminophen on a weekly basis. Acetaminophen is used in many products in combination with other preparations, especially with opioids and diphenhydramine. Many people are not aware that it is contained in these combination medications. [1][2][3]

Acetaminophen is an antipyretic analgesic with a mechanism of action different from NSAIDs. Its mode of action is not clearly understood, but it appears to inhibit cyclooxygenase (COX) in the brain selectively. This results in its ability to treat fever and pain. It may also inhibit prostaglandin synthesis in the central nervous system (CNS). Acetaminophen directly acts on the hypothalamus producing an antipyretic effect.[4]

Etiology

Even though acetaminophen has a good safety profile at therapeutic levels, it can cause severe liver toxicity if taken in large amounts. The recommended dose of acetaminophen for adults is 650 mg to 1000 mg every 4 to 6 hours, not to exceed 4 grams/day. In children, the dose is 15 mg/kg every 6 hours, up to 60 mg/kg/day. Toxicity develops at 7.5 g/day to 10 g/day or 140 mg/kg.[5]

Epidemiology

Acetaminophen toxicity is the second most common cause of liver transplantation worldwide and the most common in the U.S. It is responsible for 56,000 emergency department visits, 2600 hospitalizations, and 500 deaths per year in the United States. Fifty percent of these are unintentional overdoses.[6][7][8]

Although acetaminophen poisoning is more common in children, adults often present with a more serious and fatal presentation.[9]

Pathophysiology

Acetaminophen is rapidly absorbed from the gastrointestinal (GI) tract and reaches therapeutic levels in 30 minutes to 2 hours. Overdose levels peak at 4 hours unless other factors could delay gastric emptying, such as a co-ingestion of an agent that slows gastric motility or if the acetaminophen is in an extended-release form.[5]

Acetaminophen has an elimination half-life of 2 hours but can be as long as 17 hours in patients with hepatic dysfunction. It is metabolized by the liver, where it is conjugated to nontoxic, water-soluble metabolites that are excreted in the urine.[10]

Histopathology

The histological features of acetaminophen toxicity will reveal cytolysis and the presence of centrilobular necrosis. The injury to the latter is chiefly due to the elevated levels of N-acetyl-p-benzoquinone imine (NAPQI) in this zone. [11]

Toxicokinetics

Metabolism primarily occurs through glucuronidation and sulfuration, both of which occur in the liver. In an overdose, these pathways are saturated, and more acetaminophen is subsequently metabolized to NAPQI by cytochrome P450. NAPQI is a toxic substance that is safely reduced by glutathione to nontoxic mercaptate and cysteine compounds, which are then renally excreted. An overdose depletes the stores of glutathione, and once they reach less than 30% of normal, NAPQI levels increase and subsequently bind to hepatic macromolecules causing hepatic necrosis. This is irreversible.[12][13]

Many anti-epileptic and anti-tuberculosis medications are known to increase the activity of cytochrome P450. There is also increased activity of this enzyme in alcoholics and smokers, although acute intoxication with alcohol or cirrhosis can decrease the activity of cytochrome P450.[14]

Glucuronidation is dependent on carbohydrate stores, and more acetaminophen is converted to NAPQI in the malnourished patient. There are also decreased stores of glutathione in alcoholics and patients with AIDS.

History and Physical

The clinical course of acetaminophen toxicity is divided into four stages.[15]

• During the first stage (30 min to 24 hours), the patient may be asymptomatic or may have emesis.

• In the second stage (18 hours to 72 hours), there may be emesis plus right upper quadrant pain and hypotension.

• In the third stage (72 hours to 96 hours), liver dysfunction is significant with renal failure, coagulopathies, metabolic acidosis, and encephalopathy. Gastrointestinal (GI) symptoms reappear, and death is most common at this stage.

• The fourth stage (4 days to 3 weeks) is marked by recovery.

Evaluation

The diagnosis of acetaminophen toxicity is based on serum levels of the drug, even if there are no symptoms. Other laboratory studies needed include liver function tests (LFTs) and coagulation profile (PT/INR). If the ingestion is severe, LFTs can rise within 8 to 12 hours of ingestion. Normally LFTs remain elevated in the second stage at 18 to 72 hours. Co-ingestions can be important, and a urine drug screen, EKG, and metabolic panel may be useful. If serum levels fall into the toxic range based on the Rumack-Matthew Nomogram, then treatment should be initiated. A level greater than 150 mcg/mL at 4 hours from ingestion is considered toxic. Serum levels must be drawn between 4 to 24 hours from the time of ingestion to use the nomogram properly. It can also only be applied to single acute ingestion.[16][17][18]

For chronic acetaminophen ingestions, the Rumack-Matthew Nomogram cannot be applied. Acetaminophen levels do not correlate well with the degree of overdose. In these cases, the provider must use risk factors, lab values, and clinical suspicion to determine whether or not there was significant ingestion. Suspect and treat an overdose if the acetaminophen level is greater than 20 mcg/mL or if LFTs are elevated. There is usually less toxicity as the liver can regenerate its glutathione stores.

Treatment / Management

The treatment of acetaminophen poisoning depends on when the drug was ingested. If the patient presents within 1 hour of ingestion, GI decontamination may be attempted. In alert patients, activated charcoal can be used. Orogastric lavage or whole bowel irrigation is not effective.[19][20][21]

All patients with high levels of acetaminophen need admission and treatment with N-acetyl-cysteine (NAC). This agent is fully protective against liver toxicity if given within 8 hours after ingestion. NAC works through multiple routes. It prevents the binding of NAPQI to hepatic macromolecules, acts as a substitute for glutathione, is a precursor for sulfate, and reduces NAPQI back to acetaminophen. Indications for NAC include serum levels that fall in the toxic range according to the Rumack-Matthew nomogram, an APAP level greater than 10 mcg/mL with an unknown time of ingestion, a dose of acetaminophen greater than 140 mg/kg taken more than 8 hours ago,  abnormal labs with ingestion more than 24 hours ago, and ingestion with any evidence of liver injury. [22]

NAC can be administered both intravenously (IV) and orally. The IV form has been shown to decrease the length of the hospital stay and may be better tolerated by the patient as the oral form has a foul rotten egg odor and taste. The oral form also requires 18 doses given 4 hours apart, with the total treatment time being 72 hours. In comparison, the IV form requires only 20 hours of treatment. The IV form also is preferred in pregnant patients and when there is a fulminant hepatic failure.

Patients who continue to have deterioration such as renal failure, metabolic acidosis, encephalopathy, and coagulopathy should have a referral to a transplant surgeon. In patients who present 24 hours after the ingestion of acetaminophen, NAC administration should still be attempted and may improve survival. At this stage, it can act as an antioxidant that diminishes hepatic necrosis, decreases neutrophil infiltration, improves microcirculatory blood flow, and increases tissue oxygen delivery. Hemodialysis can also be an effective treatment, especially with concurrent renal failure.  

There is no need to adjust the dose for patients with alcoholism or the chronically ill, and it is safe during pregnancy. Repeat acetaminophen levels are also not needed after treatment has begun. 

NAC should be continued past 72 hours if there is a fulminant hepatic failure until the patient receives a liver transplant, recovers, or dies.[23][24]

Differential Diagnosis

Following are some of the important differential diagnoses that need to be considered when dealing with acetaminophen toxicity:

• Hepatorenal syndrome

• Viral hepatitis

• Wilson disease

• Pancreatitis

• Emergent management of pancreatitis

• Acute tubular necrosis

• Amatoxin toxicity

• Cytomegalovirus infection

• Gastroenteritis

• Peptic ulcer disease

• Viral hepatitis

• Wilson disease

Prognosis

If the patient is diagnosed and treated promptly, the mortality for acetaminophen toxicity is less than 2%. However, if patients present late and have developed severe liver failure, the mortality is high. About 1% to 3% of patients with severe liver failure need to undergo a liver transplant as a life-saving measure.[25][26][27]

In general, children less than 6 years of age have a better prognosis than adults, chiefly because of their greater capacity to detoxify APAP. The overall prognosis of patients depends on the following criteria:

• Creatinine levels of more than 3.4 mg/dL

• Arterial pH remaining less than 7.3 despite adequate fluid hydration

• Prothrombin time more than 1.8 times control or an INR of more than 6.5

• Development of grade 3 or 4 encephalopathy

Complications

Acetaminophen can cause dangerous skin reactions. These include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP). These conditions are extremely painful and can lead to blindness and death. Acetaminophen can lead to acute liver failure, which may only be treated with an emergent liver transplant.

Deterrence and Patient Education

It is crucial to increase awareness and understanding of the general population with regards to acetaminophen dosing and toxicity. The nurse and pharmacist play an important role in educating the family about the toxicity of acetaminophen. Acetaminophen should be kept out of reach of children.

Enhancing Healthcare Team Outcomes

In general, all drug toxicities are managed with an interprofessional team of healthcare professionals. Besides physicians, the role of the nurse and pharmacist cannot be overstated. The nurse and pharmacist are key players in educating the family about the potential toxicity of acetaminophen. The parents should be informed that acetaminophen must be placed out of reach of children. In addition, the parents have to know the proper dosing for children and appreciate the fact that there are pediatric and adult doses of the drug. When patients are discharged, they should be provided with clear instructions on drug dosage, frequency, and route of administration. All parents should be educated on reading the label of the vial containing the medication. Finally, parents need to be educated that combining drugs can also increase the risk of toxicity, and this practice should be avoided.[28][29]

Review Questions

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References

1.

Athersuch TJ, Antoine DJ, Boobis AR, Coen M, Daly AK, Possamai L, Nicholson JK, Wilson ID. Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective. Toxicol Res (Camb). 2018 May 08;7(3):347-357. [PMC free article: PMC6062253] [PubMed: 30090586]

2.

Jasani B, Weisz DE, McNamara PJ. Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants. Semin Perinatol. 2018 Jun;42(4):243-252. [PubMed: 29958702]

3.

Rajaram P, Subramanian R. Management of Acute Liver Failure in the Intensive Care Unit Setting. Clin Liver Dis. 2018 May;22(2):403-408. [PubMed: 29605074]

4.

Ghanem CI, Pérez MJ, Manautou JE, Mottino AD. Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res. 2016 Jul;109:119-31. [PMC free article: PMC4912877] [PubMed: 26921661]

5.

Ye H, Nelson LJ, Gómez Del Moral M, Martínez-Naves E, Cubero FJ. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol. 2018 Apr 07;24(13):1373-1385. [PubMed: 29632419]

6.

Caparrotta TM, Antoine DJ, Dear JW. Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature. Eur J Clin Pharmacol. 2018 Feb;74(2):147-160. [PMC free article: PMC5765191] [PubMed: 29067481]

7.

Chiew AL, Domingo G, Buckley NA, Stathakis P, Ress K, Roberts DM. Hepatotoxicity in a child following an accidental overdose of liquid paracetamol. Clin Toxicol (Phila). 2020 Nov;58(11):1063-1066. [PubMed: 32067495]

8.

Penna A, Buchanan N. Paracetamol poisoning in children and hepatotoxicity. Br J Clin Pharmacol. 1991 Aug;32(2):143-9. [PMC free article: PMC1368435] [PubMed: 1931463]

9.

Moriya K, Tamai M, Koga T, Tanaka T, Tagawa YI. Acetaminophen-induced hepatotoxicity of cultured hepatocytes depends on timing of isolation from light-cycle controlled mice. Genes Cells. 2020 Apr;25(4):257-269. [PubMed: 32012396]

10.

Wang YX, DU Y, Liu XF, Yang FX, Wu X, Tan L, Lu YH, Zhang JW, Zhou F, Wang GJ. A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition. Chin J Nat Med. 2019 Jul;17(7):517-524. [PubMed: 31514983]

11.

Guengerich FP. Cytochrome P450 2E1 and its roles in disease. Chem Biol Interact. 2020 May 01;322:109056. [PMC free article: PMC7217708] [PubMed: 32198084]

12.

More SS, Nugent J, Vartak AP, Nye SM, Vince R. Hepatoprotective Effect of ψ-Glutathione in a Murine Model of Acetaminophen-Induced Liver Toxicity. Chem Res Toxicol. 2017 Mar 20;30(3):777-784. [PubMed: 28165728]

13.

Jiang Y, Zhang T, Kusumanchi P, Han S, Yang Z, Liangpunsakul S. Alcohol Metabolizing Enzymes, Microsomal Ethanol Oxidizing System, Cytochrome P450 2E1, Catalase, and Aldehyde Dehydrogenase in Alcohol-Associated Liver Disease. Biomedicines. 2020 Mar 04;8(3) [PMC free article: PMC7148483] [PubMed: 32143280]

14.

Saccomano SJ. Acute acetaminophen toxicity in adults. Nurse Pract. 2019 Nov;44(11):42-47. [PubMed: 31651762]

15.

McGill MR, Jaeschke H. Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation. Expert Rev Mol Diagn. 2018 Sep;18(9):797-807. [PMC free article: PMC6288799] [PubMed: 30080986]

16.

Radke JB, Algren DA, Chenoweth JA, Owen KP, Ford JB, Albertson TE, Sutter ME. Transaminase and Creatine Kinase Ratios for Differentiating Delayed Acetaminophen Overdose from Rhabdomyolysis. West J Emerg Med. 2018 Jul;19(4):731-736. [PMC free article: PMC6040894] [PubMed: 30013711]

17.

Levine M, Stellpflug SJ, Pizon AF, Peak DA, Villano J, Wiegand T, Dib C, Thomas SH. Hypoglycemia and lactic acidosis outperform King’s College criteria for predicting death or transplant in acetaminophen toxic patients. Clin Toxicol (Phila). 2018 Jul;56(7):622-625. [PubMed: 29301418]

18.

Alempijevic T, Zec S, Milosavljevic T. Drug-induced liver injury: Do we know everything? World J Hepatol. 2017 Apr 08;9(10):491-502. [PMC free article: PMC5387361] [PubMed: 28443154]

19.

Janssen J, Singh-Saluja S. How much did you take? Reviewing acetaminophen toxicity. Can Fam Physician. 2015 Apr;61(4):347-9. [PMC free article: PMC4396760] [PubMed: 25873702]

20.

Imani F, Motavaf M, Safari S, Alavian SM. The therapeutic use of analgesics in patients with liver cirrhosis: a literature review and evidence-based recommendations. Hepat Mon. 2014 Oct;14(10):e23539. [PMC free article: PMC4250965] [PubMed: 25477978]

21.

Fukumoto M. [Are nomograms available for the treatment of acetaminophen poisoning? Limitation of Rumack & Matthew nomogram for evaluation of hepatotoxicity]. Chudoku Kenkyu. 2010 Jun;23(2):111-5. [PubMed: 20593648]

22.

Muñoz Romo R, M Borobia Pérez A, A Muñoz M, Carballo Cardona C, Cobo Mora J, Carcas Sansuán AJ. Efficient diagnosis and treatment of acute paracetamol poisoning: cost-effectiveness analysis of approaches based on a hospital toxicovigilance program. Emergencias. 2018 Jun;30(3):169-176. [PubMed: 29687671]

23.

Yesil Y, Ozdemir AA. Evaluation of the children with acute acetaminophen overdose and intravenous N-acetylcysteine treatment. Pak J Med Sci. 2018 May-Jun;34(3):590-594. [PMC free article: PMC6041551] [PubMed: 30034421]

24.

Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018 Feb 23;2(2):CD003328. [PMC free article: PMC6491303] [PubMed: 29473717]

25.

Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J Clin Transl Hepatol. 2016 Jun 28;4(2):131-42. [PMC free article: PMC4913076] [PubMed: 27350943]

26.

Frischknecht J. Order in the house. Setting standards for treatment of acetaminophen toxicity. Adv NPs PAs. 2013 Mar;4(3):34-6. [PubMed: 23516749]

27.

Chan TY, Tam HP, Lai CK, Chan AY. A multidisciplinary approach to the toxicologic problems associated with the use of herbal medicines. Ther Drug Monit. 2005 Feb;27(1):53-7. [PubMed: 15665747]

28.

O’Malley P. Too much of a good thing: paracetamol (acetaminophen) toxicity: update for the clinical nurse specialist. Clin Nurse Spec. 2005 Jan-Feb;19(1):18-9. [PubMed: 15684889]

Disclosure: Suneil Agrawal declares no relevant financial relationships with ineligible companies.

Disclosure: Babak Khazaeni declares no relevant financial relationships with ineligible companies.

Acute Paracetamol (Acetaminophen) Poisoning in Children uMEDp

Drug-induced liver injury is a rare but life-threatening event. Paracetamol is one of the drugs with a direct dose-dependent hepatotoxic effect.
The purpose of the study is to study the clinical manifestations and laboratory parameters in acute paracetamol poisoning in children.
Material and methods. A clinical assessment of the condition of patients was carried out, anamnestic data were analyzed. Laboratory research methods included general and biochemical blood tests. The acid-base state, the international normalized ratio were studied. Chemical-toxicological examination of urine was performed by thin-layer chromatography.
Results. Acute paracetamol poisoning in children develops when the drug is taken simultaneously at a dose of more than 3 g. In the first phase of the disease (10-11 hours after the use of paracetamol), neurosensory and general somatic disorders occur in patients. In the second phase (12–24 hours), disorders of the gastrointestinal tract and liver damage in the form of acute hepatitis of a mild degree of activity predominate.

Fig. 1. Metabolism of paracetamol

Table 1. Clinical symptoms of acute paracetamol poisoning in 20 children aged 11 to 17 years 11 months

Fig. 2. Dynamics of the main clinical symptoms of paracetamol poisoning in 20 children aged 11 to 17 years 11 months

Table 2. Biochemical parameters of blood in acute paracetamol poisoning in 20 children aged 11 to 17 years 11 months

Table 3. Indicators of the acid-base state in acute paracetamol poisoning in 20 children aged 11 to 17 years 11 months

Table 4. Clinical blood parameters in acute paracetamol poisoning in 20 children aged 11 to 17 years 11 months

Hepatotoxicity of drugs remains the leading cause of acute liver failure (ARF) in many countries around the world. Paracetamol poisoning accounts for nearly 50% of all cases of AKI in the US and UK, according to the Research Group Registry [1, 2]. In the United States, paracetamol overdose is the leading cause of visits to poison control centers (up to 100,000 per year), more than 56,000 emergency calls, 26,000 hospitalizations, and an annual cause of almost 450 deaths due to ARF [3-5].

Paracetamol (Acetaminophen) refers to non-narcotic painkillers/antipyretics, is available separately or is included in combined drugs [6]. Paracetamol was first synthesized in 1893. In 1955, the drug was introduced for clinical use and became widely used almost all over the world. Information about the hepatotoxicity of paracetamol first appeared in the 1960s. Due to its easy availability and lack of need for a doctor’s prescription, paracetamol has become one of the most common drugs used for suicidal purposes. Accidental poisoning is also possible in case of an overdose of the drug due to uncontrolled self-medication or medical error [7].

Risk factors for the occurrence of toxic effects when taking paracetamol include chronic liver disease, cardiovascular insufficiency, alcohol intake, pregnancy, protein-energy malnutrition, starvation, taking drugs that induce microsomal liver enzymes (barbiturates, chlorpromazine, carbamazepine, isoniazid, etc.) . As a result of the induction of microsomal liver enzymes, the metabolism of paracetamol is accelerated, which contributes to an increase in the total amount of toxic metabolites. If from an overdose of paracetamol, mortality from acute renal failure is 60%, then with the previous intake of inducer drugs, it can reach 98% [8]. Starvation slows down the formation of various antioxidants, primarily glutathione, reduces glycogen stores, induces CYP2E1, reduces the intensity of glucuronyl transferase formation, which leads to impaired drug binding, its oxidation and detoxification [9].

Paracetamol is metabolized in the liver due to glucuronide and sulfate conjugation (up to 80%). In a small amount, paracetamol is converted by microsomal enzymes of the cytochrome P450 system into a highly reactive N-acetyl-p-benzoquinoneimine derivative (N-acetyl-p-benzoquinoneimine – NAPQI) (Fig. 1). Glutathione quickly neutralizes this substance, converting it into a cysteine ​​or mercapturine conjugate. Taking a high dose of the drug causes saturation of the sulfate and glucuronide pathways of metabolism and an increase in the amount of its toxic derivative – NAPQI. When the content of glutathione decreases below a critical level (approximately 30% of the normal supply), NAPQI covalently binds to hepatocyte macromolecules, mitochondrial proteins, causing liver tissue necrosis.

For adult patients, the recommended maximum safe dose of paracetamol is ≤ 4 g per day, for children – 60 mg / kg. Paracetamol is characterized by a direct dose-dependent hepatotoxic effect. Therefore, single doses of more than 7–10 g in adults and 150 mg/kg in children can cause severe hepatocellular necrosis. shown. that doses of 15 g/day in adults and 200 mg/kg in children are fatal in 80% of cases [10]. In turn, in patients with alcohol dependence, a daily dose of 2–6 g is associated with lethal hepatotoxicity [11].

According to the literature, significant damage to hepatocytes by paracetamol in children is relatively less common than in adults, and occurs in 10% of cases when potentially toxic doses of the drug are taken [12].

Clinical signs of paracetamol hepatotoxicity can be divided into four phases [8, 13]. The first phase occurs within a few hours after taking the drug. It is characterized by general symptoms (malaise, increased sweating, tachycardia, sometimes vascular collapse, drowsiness) and gastrointestinal (abdominal pain, nausea, vomiting). Liver function tests show a slight increase in the level of aminotransferases – alanine aminotransferase (ALT) and aspartate aminotransferase (AST) approximately 12 hours after the use of the drug. The second phase is from 24 to 48 hours after taking paracetamol. During this period, patients may feel well, and symptoms are often absent. In a number of patients, the level of transaminases continues to rise. The third phase develops after two to five days with severe liver damage. In addition to gastrointestinal symptoms, it is characterized by hepatic encephalopathy, lethargy, jaundice, dark urine, coagulopathy, metabolic acidosis with the development of multiple organ failure, leading to death. The fourth phase is recovery, which occurs on the fifth to tenth day after taking paracetamol.

The purpose of the study is to study the clinical manifestations and laboratory parameters in acute paracetamol poisoning in children.

Material and methods

To solve this problem, we analyzed the case histories (form No. 003 / y) of 20 children (12 girls and 8 boys) aged 11 to 17 years 11 months with acute paracetamol poisoning (T39.1 according to the International Classification of Diseases of the 10th revision ), who were treated in the toxicology department of the Children’s City Clinical Hospital No. N.F. Filatov. Upon admission to the department, a clinical assessment of the condition of patients, analysis of anamnestic data and laboratory tests were performed. A clinical blood test was performed on an ADVIA-2120 Bayer HealthCare LLC hematological analyzer. In the study of biochemical parameters of blood and international normalized ratio (INR), a biochemical automatic analyzer AU680 was used. The acid-base state was assessed using an analyzer of the acid-base and gas composition of the blood ABL 800 FLEX. In all victims, the diagnosis of poisoning was confirmed by the results of a chemical-toxicological study of urine using thin-layer chromatography. For statistical data processing, the STATISTICA 7.0 software package was used. Quantitative indicators are presented as a median, 25th and 75th percentile.

Research results

When analyzing the anamnestic data obtained during the examination of victims as a result of paracetamol poisoning, it was found that the average exposure of the poison in the body was 11. 0 [3.0; 17.0] hours. In 60% of cases, the condition of children upon admission to the department was assessed as moderate, in 20% of cases – severe. At the same time, children admitted to the department in serious condition had a longer exposure to poison (from 20 to 45 hours). The dose of paracetamol taken ranged from 5 to 20 g. The frequency of occurrence of clinical symptoms of paracetamol poisoning is presented in Table. 1. As you can see, 85% of patients complained of weakness, general malaise, lethargy. In 60% of cases, nausea, urge to vomit were recorded, in 50% – pallor of the skin, pain on palpation in the epigastric region, and vomiting. The dynamics of the main toxic effects of paracetamol is shown in Fig. 2.

In the initial stage of poisoning (after 10–11 hours from the moment of taking paracetamol), the first clinical manifestations of the disease were noted in patients in the form of neurosensory and general somatic disorders (headache, weakness, pallor of the skin). After 12–17 hours, the clinical picture of the disease was dominated by signs of damage to the gastrointestinal tract: nausea, repeated vomiting, pain in the right hypochondrium and epigastric region.

With a longer exposure to poison (19-45 hours) in severe patients, tachycardia from 90 to 122 beats per minute and a decrease in blood pressure (systolic from 80 to 50 mmHg) were noted.

Table 2 shows the results of a study of blood biochemical parameters in the first 12–24 hours from the moment patients enter the toxicology department. As can be seen from Table. 2, in the department of children, an increase in the level of hepatic transaminases was noted. The content of ALT in blood plasma reached an average of 80.9 [10.7; 98.0] U/l. In 15% of cases, the level of ALT in the blood serum exceeded the normal values ​​by 6–8 times, reaching a maximum value of 464.4 U/L. The AST level also exceeded normal values ​​and averaged 64.4 [16.0; 78.0] U/l, the maximum values ​​were noted at the level of 234 U/l.

In 15% of patients, an increase in the level of total bilirubin over 26 µmol/l was noted. At the same time, it should be noted that in the history of such children there was a hereditary disease associated with a defect in the gene involved in the metabolism of bilirubin (Gilbert’s syndrome). In addition, 25% of children with acute paracetamol poisoning had moderate hyperglycemia (not more than 12 mmol/l) and a decrease in cholesterol levels from 3 to 2.2 mmol/l. The INR level in all children was within the reference values ​​and averaged 1.05.

When examining the acid-base state, 55% of the victims showed an increase in lactate levels over 1.9 mmol/l (Table 3). In severe patients with severe clinical manifestations of the disease, metabolic acidosis was observed.

When examining a clinical blood test on the first day of the disease, there were no significant changes in the indicators (Table 4). However, in 30% of patients, activation of nonspecific mechanisms of phagocytic defense in the form of neutrophilic leukocytosis was recorded already in the first 24 hours of the disease.

Against the background of complex therapy, which included gastric lavage, bowel cleansing (cleansing enemas), gastroenterosorption (activated charcoal intake 30–40 minutes before the start of specific antidote therapy), specific antidote therapy with N-acetylcysteine, forced diuresis with alkalinization of blood plasma, relief was noted symptoms of intoxication and normalization of biochemical parameters by the fifth – seventh day after acute paracetamol poisoning. The children were discharged home under the supervision of a pediatrician and a gastroenterologist at the place of residence.

Conclusion

The results of our study showed that in children over 11 years of age, acute paracetamol poisoning develops with a single dose of the drug in a dose of more than 3 g. Depending on the clinical course, two phases of the disease can be distinguished. The first develops within 10-11 hours from the moment of taking paracetamol. As a rule, neurosensory and general somatic disorders are detected in patients. In some cases, clinical manifestations of intoxication do not subsequently develop. In the second phase of the disease (12–24 hours), there are disorders of the gastrointestinal tract in the form of pain, nausea, vomiting, and liver damage with the development of hepatocellular hepatitis.

Thus, after taking toxic doses of paracetamol, all patients need emergency hospitalization for specific detoxification therapy under the control of blood biochemical parameters, regardless of the severity of clinical manifestations.

Conflict of interest: the authors of the article confirmed the absence of a conflict of interest and financial support for the study, which must be reported.

Interventions for paracetamol (acetaminophen) overdose

Review question: In this review, we reviewed the evidence for interventions (treatments) used for paracetamol (acetaminophen) poisoning in humans. Basically, we tried to evaluate the impact of these interventions on the number of deaths and the need for liver transplantation.

Relevance: paracetamol is one of the most commonly used over-the-counter medications. Deliberate or accidental poisoning with paracetamol is a common cause of liver damage.

Search date: evidence is current to January 2017.

Study characteristics: randomized clinical trials (studies in which people are randomly assigned to one of two or more treatment groups) in which participants sought medical attention because they took an overdose of paracetamol, intentionally or accidentally, regardless on the amount of paracetamol taken, age, sex or other medical conditions of the patient.

There are many different interventions that can be used to treat people with paracetamol poisoning. These interventions are aimed at reducing the absorption [absorption] of paracetamol in the digestive tract and, therefore, reducing the amount of paracetamol that enters the bloodstream. These remedies include activated charcoal (which binds paracetamol in the stomach), gastric lavage (to remove as much paracetamol from the stomach as possible), or ipecacuan (a syrup that causes vomiting (nausea) when taken by mouth). After absorption, paracetamol enters the liver through the bloodstream, where most of it breaks down into safe components. However, a small part of this drug is converted into a toxic product that the liver can usually handle, but taking large amounts of paracetamol is too much for the liver. As a result, the toxic product can damage the liver and lead to liver failure, kidney failure, and in some cases death. Other interventions to treat paracetamol poisoning include drugs (antidotes) that can reduce the amount of toxic products (eg, the drug cimetidine) or break down toxic products (include drugs such as methionine, cysteamine, dimercaprol, or acetylcysteine). Finally, attempts may be made to remove paracetamol and its toxic products from the bloodstream using special blood purification equipment. All of these treatments have been studied.

We found 11 randomized clinical trials with 700 participants. Most of these trials looked at different types of treatment.

Key Findings: activated charcoal, gastric lavage, and ipecac can reduce paracetamol absorption when administered within one to two hours of paracetamol ingestion, but the clinical benefit is unclear. Activated charcoal is probably the best choice if the person can take it. Sometimes people can’t take activated charcoal by mouth because they’re drowsy, or because they don’t like the taste, the texture, or both.

Of the treatments aimed at removing paracetamol toxic products, acetylcysteine ​​is likely to reduce the incidence of liver damage from paracetamol poisoning. In addition, it has fewer side effects than other antidotes such as dimercaprol and cysteamine; its advantage over methionine was unclear. Acetylcysteine ​​should be given to people with paracetamol poisoning at risk of liver damage, the risk depending on the dose taken, meal times and laboratory data.

More recent clinical trials have looked at ways to reduce the incidence of side effects with intravenous (through a vein) administration of acetylcysteine ​​by changing the route of administration. These clinical trials have shown that using a slower infusion and a low initial dose of acetylcysteine ​​can reduce the proportion of side effects such as nausea, vomiting, and allergies (unwanted body reactions to the drug, such as rash).