PRINCIPLES OF ACETAMINOPHEN POISONING
A condition marked by liver necrosis after consuming excessive amounts of paracetamol. Acetaminophen toxicity clinical manifestations are divided into four stages based on the time since consumption. The majority of paracetamol poisoning results from a single, big dose, although it can also happen from smaller doses in people who routinely abuse alcohol, have chronic malnutrition, or take drugs that affect hepatic metabolism. The hepatic system is predominantly affected by toxicity, which is likely to occur with doses greater than 12 g in adults and more than 250 mg/kg in children. Rarely, cardiotoxicity and nephrotoxicity may occur, but there is little conclusive proof that these organ systems have been specifically damaged. A similar term is "paracetamol poisoning." EPIDEMIOLOGY Intentional ingestion accounted for 67% of hospitalisations for paracetamol toxicity from 1998 to 2011; accidental ingestion accounted for 16% of cases, and unspecified causes accounted for 17% (1). 83% of hospitalisations for paracetamol toxicity from 1998 to 2011 were for adults, and 69% of those patients were female (95% CI: 68–69%) (1). ● About 49% of unintended acetaminophen-related poison control calls between 2008 and 2012 involved children under the age of five (1). Incidence Prior to 2009, hospitalisation rates for paracetamol use gradually rose. In 2011, there were 108.6 discharges for every 100,000 people, down from 119.8 for every 100,000 in 2009 (1). Prevalence Data from the American Association of Poison Control show that there were on average 111,632 acetaminophen-related occurrences each year nationwide from 2008 to 2012 (1). According to estimates, 10% of these incidents had liver damage, and 1% had fatal outcomes (1). PATHOPHYSIOLOGY AND AETIOLOGY Pharmacokinetics Acetaminophen is completely absorbed from the duodenum during oral therapeutic ingestion and reaches peak serum concentrations of 10 to 20 g/mL within as little as 2 hours. Toxic ingestions may cause this peak to be delayed. Acetaminophen therapeutic adult doses range from 325 to 1,000 mg every four to six hours, with a daily maximum of 4 g. Therapeutic paediatric doses are 10 to 15 mg/kg every four to six hours, with a maximum of five doses per day or 75 g/kg per day. The elimination half-life of paracetamol is 2 to 4 hours, while extended-release formulations have the potential to postpone this time. PathophysiologyAcetaminophen poisoning and the ensuing hepatic damage are brought on by the consumption of supratherapeutic quantities of acetaminophen or subtherapeutic doses in people with impaired liver function. 96% of acetaminophen consumed is metabolised by the liver, and just 2-4% is eliminated in urine unaltered. N-acetyl-p-benzoquinone imine (NAPQI), a hazardous metabolite, accounts for 5- 10% of the breakdown of therapeutic dosages and 90-95% of the breakdown of benign metabolites. NAPQI quickly combines with glutathione stored in the liver to generate a harmless metabolite that is eliminated in the urine. Consuming excessive amounts of acetaminophen damages hepatocellular tissue by overloading the glucuronidation and sulfation pathways, diminishing glutathione reserves. RISK FACTORS include concurrent toxicity with other substances that affect hepatic metabolism, mental illness or a history of suicide attempts, excessive alcohol consumption on a regular basis, chronic malnutrition, and potential risks from prior weight loss surgery. DURATIONAL PREVENTION Poison Control can be reached at (800) 222-1222 for advice and consultations. FDA labelling recommendations are available at: http://www.fda.gov/ Drugs/ GuidanceCompliance RegulatoryInformation/ Guidances/ default.htm. Aspects of Geriatrics Due to impaired hepatic metabolism and concomitant administration of other hepatotoxic drugs, there is an increased risk of liver injury in frail, elderly individuals. people with liver illness, alcohol consumption disorders, and/or elderly people should not take more than 3,000 mg of paracetamol each day. Child Safety Considerations Young children may experience less severe liver damage from hazardous paracetamol doses, maybe because they have larger glutathione reserves. pregnant women's issues Acetaminophen intoxication increases the risk of spontaneous abortion in pregnant women, especially when the overdose occurs at a young gestational age. Delaying acetylcysteine (NAC) medication increases the risk of abortion and potential foetal mortality. Because IV NAC has a higher bioavailability during pregnancy, it is often favoured. DIAGNOSIS Poisoning signs and symptoms appear within the first 24 hours of significant ingestions. In those who have a history of long-term consumption of doses close to supratherapeutic doses, symptoms may appear gradually. There are four stages in which symptoms can present themselves (3). Stage 1: the first 24 hours following consumption Patient may have no symptoms for the first eight hours after ingesting. Nausea, emesis, anorexia, and diaphoresis are possible symptoms. – At this point, laboratory findings are typically uninteresting. Stage 2—days two to three after intake Right upper quadrant pain and hepatomegaly may become obvious. - Usually less nausea, vomiting, diaphoresis, and malaise than in stage 1. – Usually, elevated aminotransferases are detected. Stage 3—days three to four after intake - Recurrence of Stage I symptoms such nausea, vomiting, and malaise. – Jaundice, disorientation, sleepiness, and coma are possible symptoms of severe poisonings. - Significant increases in liver enzymes that normally peak at this time; extended PT/INR; and frequently low paracetamol levels – In this stage, multiorgan failure and death are most frequent. Stage 4: days 5+ following ingestion - A potential stage of recovery in patients whose stage 3 symptoms are subsiding - Recovery may take a while, but it usually goes smoothly and without any aftereffects. Laboratory anomalies usually go away. - Fulminant hepatic failure is extremely rare in children under the age of six and occurs in about 1% of adults. HISTORY What was ingested (extended release, hydrocodone-acetaminophen, coingestants, etc.), how much was ingested, and when was ingested should be the main topics of inquiry. Was the ingesting deliberate or unintentional? Additionally, inquire about any past or present hepatitis, alcohol addiction, and surgery. MEDICAL ANALYSIS The results of a physical test may probably change depending on the level of toxicity. A thorough physical examination is generally necessary, along with a vitals assessment. Examine the person's general appearance for indicators of dehydration, such as diaphoresis, pallor, weariness, and somnolence. Look out for hepatomegaly and RUQ discomfort, which are symptoms of hepatotoxicity. DISTINCTIVE DIAGNOSIS Amanita phalloides, products containing yellow phosphorus or carbon tetrachloride, as well as other ingested toxins that cause severe acute hepatic injury, should all be taken into account. You should also take into account the presence of coingestants, especially alcohol, opiates, and aspirin. DETECTION & INTERPRETATION OF DIAGNOSIS Initial examinations (lab, imaging) All patients should have their plasma paracetamol levels measured 4 hours after administration (the peak time). If an extended-release version was consumed, draw additional levels at 6 and 8 hours. The frequency of physical examinations, vital signs checks, and any additional tests that might be necessary can be guided by Poison Control (3). – Obtain two serum paracetamol values, 4 to 6 hours apart, if a sustained-release product has been consumed. If either level exceeds the potential toxicity line, treat. – Treat patients with persistent toxicity or those who show up 24 hours after intake based on the clinical effects, LFTs, and acetaminophen level. Alanine transaminase (ALT), aspartate transaminase (AST), prothrombin time (PT)/international normalised ratio (INR), bilirubin, and lactate dehydrogenase (LDH) are among the liver function tests that can be performed. Along with LFT alterations, PT/INR increases with severe poisonings. – - Improvement in ALT with therapy is an optimistic clinical indicator. AST, ALT, and bilirubin levels rise with hazardous ingestions and peak in stage 3. Additional lab tests include those for serum alcohol, electrolytes, glucose, BUN, creatinine, urinalysis, and urine drug screening (UDS). - Based on the clinical history, screen for coingestants with the aforementioned labs and take additional drugs or substances into consideration. – Get a urine or serum pregnancy test in females because it may affect treatment. - Take an arterial blood gas (ABG) into consideration: Anion-gap metabolic acidosis caused by a buildup of 5-oxoproline may occasionally be observed. Imaging: No particular imaging is necessary. Tests in the Future & Special Considerations Liver tests should return to normal during the healing process, and full liver function restoration without long-term consequences is anticipated. Other/Diagnostic Procedures When acute hepatitis or renal injury are evident, advanced imaging of the liver and/or kidney with ultrasound or CT can be thought about to rule out alternative explanations. If aberrant results are discovered without imaging, they could be nonspecific. TREATMENT Request advice right away from a nearby Poison Control Centre. Dial (800) 222-1222 to reach someone in the US. NAC is a safe prodrug that gives cysteine as a substrate for the detoxification of acetaminophen metabolites and replenishes glutathione reserves in the liver. Taking NAC may lower mortality from 5% to 0.7%. According to the Rumack-Matthew nomogram (3): – A plot used to assess whether paracetamol levels during acute hazardous ingestions are high enough to call for treatment with NAC. – The nomogram is not meant for long-term use or for products with sustained release. – When paracetamol plasma levels are at the "treatment line" or above on the Rumack-Matthew nomogram and tested 4 hours after intake, provide NAC. – At 4, 8, and 12 hours after intake, the treatment line acetaminophen plasma levels on the nomogram correspond to >150 g/mL (993 mol/L), >75 g/mL (497 mol/L), and >37 g/mL (244 mol/L), respectively. Whenever possible, start NAC (Mucomyst) within 8 hours of ingestion. Single-dose activated charcoal (1 g/kg PO) may also be useful if administered within 1 to 4 hours of ingestion. Never wait to take oral NAC after taking activated carbon. The routine use of ipecac and gastric lavage at home or in healthcare settings is no longer advised. First Line: MEDICATION Start NAC empirically within 8 hours, even if you're awaiting lab results. It might still work 36 hours after consumption. NAC may be administered IV or PO, depending on the circumstance and what is available. Compared to PO NAC, IV NAC has been demonstrated to shorten hospital stays. – To lessen the negative effects of NAC treatment, a 2-bag regimen should be employed to provide a total of 300 mg/kg IV NAC (Acetadote, Cetylev) over a 20-hour period. Start by administering 200 mg/kg IV over four hours, then 100 mg/kg IV over sixteen hours (5). – Use an oral loading dosage of 140 mg/kg, followed by 17 doses of 70 mg/kg every four hours (72-hour schedule). NAC safety measures: - Due to its sulphur content, PO NAC frequently causes substantial nausea and vomiting and is poorly tolerated; try using a nasogastric tube. - Anaphylactoid reactions to IV NAC (Acetadote) are possible (3-6%) and can include rash, bronchospasm, pruritus, angioedema, tachycardia, or hypotension (atopic dermatitis and asthmatics are more likely to experience these reactions). Reactions frequently happen after the loading dose. Slow or briefly stop the infusion to avoid this; you can also treat it with antihistamines at the same time. - Metoclopramide, 1 to 2 mg/kg IV, or ondansetron, 0.15 mg/kg IV, can be used to relieve nausea. - The percentage of NAC failures varies from 3% to 7% (4). Within 1 to 4 hours of intake (particularly in situations of coingestants), administer a single dosage of activated charcoal. Don't delay administering NAC because you're using activated charcoal. Next Line Hemodialysis may increase survival in cases of severe ingestions (levels >1,000 mg/L, severe acidosis, coma/hypotension), severe renal failure, or both. QUESTIONS FOR REFERENCE Child abuse reporting if negligence resulted in an overdose; Behavioural health assessment for purposeful ingestions; CONSIDERATIONS FOR ADMISSION, THE INPATIENT, AND NURSING For hazardous ingestions accompanied by vital instability and/or test abnormalities, hospitalisation should be considered. When medically stable, take into account admission to a mental health facility for purposeful ingestions. IV fluids are typically offered to help patients stay hydrated. CONTINUING CARE AFTERCARE RECOMMENDATIONS In a hospital that has been granted accreditation, evaluate each patient. • Assess patients for emergency liver transplantation (ELT) in a transplant facility who have signs of organ failure, elevated LFTs, or coagulopathy. For nontoxic accidental ingestions, outpatient care is sufficient; limit activity if liver damage is severe. No particular diet is required, unless you have serious liver disease. EDUCATION OF PATIENTS Encourage patients to stay away from acetaminophen (Tylenol, among other brands) and other acetaminophen-containing products, especially if they are using combination products that contain acetaminophen. Inform parents and carers about proper OTC dosage and drug storage during well-child checkups. Give carers, family members, and roommates of possibly suicidal patients proactive advice. Patients should be informed about long-term paracetamol therapy. PROGNOSIS In stage 4 of toxicity, complete recovery is both achievable and more likely with early therapy (3). In 10% of adult patients with significant liver problems, necrosis, hepatic encephalopathy, or transplantation are required (1). Children under the age of six rarely get hepatic failure. COMPLICATIONS After an acute poisoning, recovery is complete, and complications are uncommon.
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