Acetaminophen Shahid Aziz MBBS, MRCP (UK), MCEM (London) Assistant Professor, DEM College of Medicine King Saud University Consultant Emergency Medicine King Khalid University Hospital

Objectives: 1-Acquire the skills of taking focused history and physical examination for acetaminophen intoxicated patients in ED 2- Acquire the basic approach to the acetaminophen poisoned patient 3- Understand the pahto physiological and pharmacological effects of acetaminophen. 4- Understand the role of healthcare professionals in poison control and prevention.

PERSPECTIVE  Acetaminophen may be found as an isolated product or in combination medications Acetaminophen

PRINCIPLES OF DISEASE  Acetaminophen is absorbed rapidly, with peak plasma concentrations generally occurring within 1 hour and complete absorption within 4 hours.  Once absorbed, acetaminophen inhibits prostaglandin E 2 (PGE 2 ) synthesis, leading to antipyresis and analgesia.  Inhibition of PGE 2 synthesis is either by direct COX-2 inhibition or inhibition of membrane- associated prostaglandin synthase

metabolized by conjugation with  glucuronide (40–67%) and  sulfate (20–46%) into nontoxic metabolites that are excreted in the urine.  A small percentage (<5%) is oxidized by cytochrome P 450 2E1 (CYP2E1) (and to a lesser extent 1A4 and 3A4) to a highly cytotoxic metabolic intermediary, N-acetyl-p- benzoquinonimine (NAPQI). PRINCIPLES OF DISEASE

 In therapeutic doses, NAPQI is short-lived, combining rapidly with glutathione and other thiol-containing compounds to form nontoxic metabolites that are excreted in the urine.  With typical therapeutic acetaminophen dosing, glutathione stores and the ability to regenerate glutathione easily keep up with NAPQI production.… PRINCIPLES OF DISEASE

 After large ingestions or repeated supratherapeutic ingestions, the amount of NAPQI produced begins to outstrip glutathione stores and the liver's ability to regenerate glutathione, leading to unbound NAPQI.  NAPQI covalently binds to critical cell proteins in the liver, which initiates a cascade of events that lead to hepatic cellular death.  Renal injury may also occur with or without liver injury and may be mediated by renal CYP (cytochrome) enzymes or activation of prostaglandin synthase. PRINCIPLES OF DISEASE

  With severe toxicity, necrosis of the entire liver parenchyma may occur.  Clinical effects of severe toxicity are the result of severe fulminant liver failure rather than a direct acetaminophen effect.  These effects include multiorgan failure, SIRS, hypotension, cerebral edema, and death PRINCIPLES OF DISEASE

 The principal therapy for acetaminophen toxicity is N-acetylcysteine (NAC) via two separate mechanisms: 1. NAC serves as a glutathione precursor and a sulfur-containing glutathione substitute, thereby detoxifying NAPQI and avoiding subsequent hepatotoxicity. 2. NAC may decrease NAPQI formation by enhancing acetaminophen conjugation with sulfate to nontoxic metabolites. PRINCIPLES OF DISEASE

 Hepatic injury, which can progress to hepatic failure and renal failure.  Early, patients may be asymptomatic or have mild nonspecific symptoms (e.g., nausea, vomiting, anorexia, malaise, diaphoresis) CLINICAL FEATURES

Time Course and Clinical Stages of Acetaminophen Toxicity

 Liver injury becomes evident after a period of 8 to 36 hours as an elevation in aspartate aminotransferase (AST).  Once liver injury has begun, patients may develop right upper quadrant (RUQ) pain or tenderness, vomiting, and jaundice.  AST concentrations continue to rise and usually peak in 2 to 4 days, corresponding to maximal liver injury. CLINICAL FEATURES

 Alanine aminotransferase (ALT), prothrombin time (PT), and bilirubin typically begin to rise and peak shortly after AST values.  In severe toxicity, AST, ALT, and the PT may all be elevated within 24 hours. CLINICAL FEATURES

 patients may develop signs and symptoms fulminant liver failure, including metabolic acidosis, coagulopathy, and hepatic encephalopathy CLINICAL FEATURES

 Death may occur from hemorrhage, ARDS, sepsis, multiorgan failure, or cerebral edema.  The risk of renal injury increases with the severity of hepatic injury, occurring in less than 2% of patients without hepatotoxicity and in 25% of patients with severe hepatotoxicity. CLINICAL FEATURES

 If patients recover, transaminases return to baseline levels over a period of 5-7 days, although complete histologic resolution of liver injury may take months.  Once histologic recovery is complete, there are no long-term sequelae to the liver and patients are not at risk for chronic hepatic dysfunction. CLINICAL FEATURES

 The primary goals of patient assessment after acetaminophen exposure are the determination of the patient's risk, diagnostic testing, and treatment with the antidote NAC when appropriate. DIAGNOSTIC STRATEGIES

 An acute ingestion is generally considered to be a single ingestion, arbitrarily defined to be occurring within a 4-hour period.  All other ingestions, including accidental repeated supratherapeutic ingestions and intentional ingestions spread over longer than 4 hours, can be considered to be chronic. DIAGNOSTIC STRATEGIES

 More than150 mg/kg in an acute ingestion must be consumed before significant liver toxicity is evident  A serum acetaminophen concentration may be considered in all intentional overdoses Risk Assessment with Acute Acetaminophen Ingestion

 Establish a time of ingestion.  If no accurate time of ingestion can be determined, a worst-case scenario should always be considered (e.g., the last time the patient was seen prior to the ingestion). Risk Assessment with Acute Acetaminophen Ingestion

 Determine a serum acetaminophen concentration 4 hours post ingestion.  The acetaminophen concentration and the time of ingestion determine the need for antidotal therapy by plotting the serum acetaminophen concentration against the time since ingestion on the treatment Rumack- Matthew nomogram Risk Assessment with Acute Acetaminophen Ingestion

Treatment nomogram for acute overdose. The lower treatment line should be used for treatment decisions. (Modified from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 55:871, 1975.)

 If the serum acetaminophen concentration is on or above the treatment line (that starts at 150 g/L at 4 hr and decreases to 4.7 g/L at 24 hr), then antidotal treatment with NAC should be initiated immediately. Risk Assessment with Acute Acetaminophen Ingestion

 If the serum acetaminophen concentration is below the treatment line and the worst case scenario has been taken for the time of ingestion, then the patient requires no antidotal therapy.  Use of the treatment line is a highly sensitive approach and may be used for all acute ingestions. Risk Assessment with Acute Acetaminophen Ingestion

 Measurement of serum acetaminophen concentration prior to 4 hs not necessary. Risk Assessment with Acute Acetaminophen Ingestion

 Fortunately, there is little need to treat patients prior to 6 to 8 hours after ingestion, as patients treated with NAC up to 6 hours after ingestion have no increased risk of hepatotoxicity regardless of their serum acetaminophen concentration. Risk Assessment with Acute Acetaminophen Ingestion

 Risk of hepatotoxicity does not significantly increase unless NAC is delayed for 8 hours or longer after ingestion.  For patients at risk whose serum acetaminophen concentration cannot be obtained prior to 6 to 8 hours after ingestion, a loading dose of NAC should be considered. Risk Assessment with Acute Acetaminophen Ingestion

 If repeated or chronic exposure treatment nomogram cannot be used.  The initial steps include determining if the patient is at risk for hepatotoxicity, evaluating the patient by measuring a serum acetaminophen concentration and an AST Risk Assessment with Chronic Ingestion

 Once serum acetaminophen concentration and AST are obtained, further risk assessment is necessary.  Conceptually, patients with chronic ingestions may benefit from antidotal therapy if they have evidence of liver injury or if they have evidence of acetaminophen excess that may lead to liver injury.  patients with chronic supratherapeutic acetaminophen exposure with significant elevations of AST (e.g., ≥50 IU) should be treated with NAC regardless of their serum acetaminophen concentration. Risk Assessment with Chronic Ingestion

 All patients who do not require antidotal therapy should be educated to return to the emergency department if they develop signs of hepatotoxicity (e.g., RUQ abdominal pain, vomiting, jaundice). Risk Assessment with Chronic Ingestion

Mainstays of management are  Supportive care  NAC therapy when indicated MANAGEMENT

 Gastric emptying by lavage is not indicated because of the very rapid absorption of acetaminophen and the availability of an effective antidote. Limiting Gastrointestinal Absorption MANAGEMENT

Activated charcoal (AC)  no evidence that administration of AC translates into improved clinical outcomes. MANAGEMENT

 When indicated, NAC should be administered as early as possible.  Delay of administration of NAC longer than 6 to 8 hours after ingestion increases the risk of hepatotoxicity. N-Acetylcysteine MANAGEMENT

 PO or IV.  Both methods are efficacious in most situations, with advantages and disadvantages for each.  All (PO or IV) are very effective when started within 6 to 8 hours of ingestion. N-Acetylcysteine MANAGEMENT

 Both PO and IV NAC are equally effective in treating patients who present 8 to 24 hours after ingestion. N-Acetylcysteine MANAGEMENT

 Once liver failure (e.g., coagulopathy, encephalopathy, etc.) is evident, however, the IV route is the only route that has been systematically studied.  IV NAC decreases the risk of hypotension, cerebral edema, and death in patients with acetaminophen-related hepatic failure. N-Acetylcysteine MANAGEMENT

 2 to 6% of patients in IV NAC develop anaphylactoid reactions  The majority of these symptoms are mild and consist of transient skin rashes and flushing. N-Acetylcysteine MANAGEMENT

 More severe reactions have been reported in less than 1%  Symptoms typically occur within 30 minutes of the start of the loading infusion.  These anaphylactoid reactions are dose-, rate-, and concentration-dependent. N-Acetylcysteine MANAGEMENT

 Any dose that is vomited within 1 hour of administration should be repeated. N-Acetylcysteine MANAGEMENT

Anaphylactoid reactions to IV NAC  typically mild (e.g., flushing) and occur during the initial 15- to 60-minute infusion.  managed with antihistamines (e.g., IV diphenhydramine) without stopping the infusion. Serious reactions can be managed by slowing or pausing the infusion, giving a fluid bolus, and administering diphenhydramine or IV glucocorticoids if necessary. Epinephrine is rarely required. N-Acetylcysteine MANAGEMENT

 Treating the mother with NAC is safe and effective, and NAC effectively crosses the placenta.  Administration of IV NAC to the mother has the theoretical advantage of increased NAC delivery to the fetus compared with PO NAC. N-Acetylcysteine in Pregnancy

Once NAC is initiated,  All large published studies have continued therapy for 72 hours and, therefore, it is difficult to recommend a shorter protocol in the absence of published experience. N-Acetylcysteine MANAGEMENT

 If a patient presents with established hepatotoxicity transfer to a higher level center that specializes in the care of patients with liver failure may be advisable, as is the case for any other patient presenting with liver failure. DISPOSITION

- Toxic dose of paracetamol is 50mg/kg. - The toxic metabolite of paracetamol is N-acetyl-P- benzoquinonimine (NAPQI) - NAC detoxifies NAPQI - Toxicity can cause liver & renal failure

- In paracetamol poisoning death may occur from, - Sepsis - Haemorrhage - ARDS - Multi organ failure - Cerebral oedema