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1252 SECTION 15: Toxicology injury from other causes. Pulmonary edema begins to improve con comitantly with the lowering of serum salicylate concentrations. Aggressive efforts toward rapid elimination by hemodialysis may be beneficial in this subset of patients. Hemodialysis enables removal of salicylate without the volume infusion that accompanies sodium bicarbonate administration; hemodialysis thus avoids the risk of volume-mediated aggravation of lung injury. When a patient with severe salicylate toxicity requires endotracheal intubation, mechanical ventilation, and sedation, it is important to maintain hyperventilation; ventilator settings should not be based on standard age- and weight-based nomograms. Before intubation and mechanical ventilation, most patients with severe salicylate toxicity have a respiratory alkalosis. Controlling the ventilatory rate and volume to “normal” ranges produces a decrease in serum pH and causes a rapid shift of salicylate into the CNS. It is important to maintain respiratory alkalosis during mechanical ventilation. Use the minimal amount of safe sedation that allows a patient to continue over-breathing the ventilator. Consider one to two ampules (88 to 100 mEq) of bicarbonate bolus immediately prior to intubation as a basic buffer for the transient decrease in ventilation that occurs during rapid-sequence induction intubation. Hemorrhagic complications are rarely seen following single massive salicylate overdoses, but chronic administration of large doses may cause significant hypoprothrombinemia. Even in this circumstance, hemor rhage is rarely seen in clinical practice. When bleeding does occur, it rarely appears to be a contributing factor in mortality from salicylate toxicity. Patients with clinically significant bleeding should be treated with fresh frozen plasma. Observations in animals and humans indicate that administering large doses of vitamin K after the development of hypoprothrombinemia has little or no effect on the prothrombin time when serum salicylate concentration is high.  HEMODIALYSIS Hemodialysis is considered the extracorporeal technique of choice for the treatment of serious salicylate toxicity because hemodialysis can correct acid-base and electrolyte abnormalities while rapidly reducing the body salicylate burden. 36,37 The inherent delays in implementing hemodialysis underline the importance of early consideration of this intervention; thoughtful planning and prompt consultation with the nephrology service are strongly advised. Indications for hemodialysis include clinical deterioration or failure of improvement despite intensive supportive care, lack of success in alkalinizing serum and urine, renal insufficiency or failure, severe acid-base disturbance, altered mental status, and acute lung injury. Consider hemodialysis for salicylism requiring respiratory and ventilatory support. Serum salicylate concentration should not be the sole determinant in the decision to initiate hemodialysis; however, patients with acute toxicity and serum salicylate concentrations >100 milligrams/dL (>7.2 mmol/L), patients with chronic toxicity with concentrations >60 milligrams/dL (>4.3 mmol/L), and symptomatic patients with lower serum salicylate concentrations should be considered candidates for hemodialysis.

odialysis; however, patients with acute toxicity and serum salicylate concentrations >100 milligrams/dL (>7.2 mmol/L), patients with chronic toxicity with concentrations >60 milligrams/dL (>4.3 mmol/L), and symptomatic patients with lower serum salicylate concentrations should be considered candidates for hemodialysis. Consider the early use of hemodialysis in patients who are elderly, have chronically ingested aspirin, have altered mental status, have acidemia, or have comorbidities (e.g., coronary artery disease or chronic obstructive pulmonary disease). Emergency hemodialysis places a significant demand on the car diovascular system, and hypotensive patients or those with underly ing cardiac disease may not be able to tolerate the hemodynamic intensity of 4-hour hemodialysis treatments. A less demanding but more prolonged therapy, such as hemofiltration, hemodiafiltration, or sustained low-efficiency dialysis, may be used until hemodialysis can be tolerated. Once initiated, extracorporeal elimination techniques should be continued until the serum salicylate level is <20 milligrams/dL (<1.4 mmol/L). DISPOSITION AND FOLLOW-UP A patient may be discharged from the ED once it can be determined that the patient had an inconsequential salicylate overdose; this requires demonstration of serial declining salicylate levels. Patients who have Acetaminophen Rachel S. Wightman Lewis S. Nelson INTRODUCTION Acetaminophen (N-acetyl-p-aminophenol or paracetamol) is the most popular over-the-counter analgesic and is one of the most common toxic exposures reported to poison centers. Acetaminophen (sometimes abbreviated APAP) is available as a sole agent or combined with a variety of other medications prepared in different forms, such as tablets, ca psules, gels, and liquids. Although most serious poisonings involve intentional self-harm, poisonings often occur because of the erroneous belief that this medication is benign or because the victim was unaware that acetaminophen was an ingredient in the ingested preparation. 1,2 In the United States, acetaminophen is the most common cause of drug-induced liver failure and accounts for almost half of all cases of acute liver failure. 3,4 Acetaminophen–opioid combination products have been implicated in chronic overuse, likely due to an increasing opioid requirement leading to concomitantly increasing acetaminophen exposure. 5 In response to these safety concerns, in 2011, the U.S. Food and Drug Administration limited the prescription acetaminophen–opioid combination preparation strength to 325 milligrams per dosage unit and now requires a boxed warning to notify consumers of the potential risk for serious liver toxicity. PHARMACOLOGY  ORAL ACETAMINOPHEN The recommended maximum total daily dose is 3900 milligrams in adults using 325-milligram acetaminophen (regular strength) and 3000 milligrams when using the 500-milligram acetaminophen (extra strength) preparation. Adults should not use acetaminophen for more than 10 consecutive days unless directed by their physician. For children, the recommended acetaminophen dose is 10 to 15 milligrams/kg every 4 to 6 hours as needed, with a maximum daily dose of 75 milligrams/kg or five doses in a 24-hour period. Patients with insufficient glutathione stores (e.g., alcoholics and acquired immunodeficiency syndrome patients) and patients with induced cytochrome P450 (CYP450) enzymatic activity (e.g., alcohol ics and those taking concurrent anticonvulsant or antituberculous medications) may be at greater risk for developing acetaminopheninduced hepatotoxicity following overdose (as opposed to therapeutic dosing described earlier).

patients) and patients with induced cytochrome P450 (CYP450) enzymatic activity (e.g., alcohol ics and those taking concurrent anticonvulsant or antituberculous medications) may be at greater risk for developing acetaminopheninduced hepatotoxicity following overdose (as opposed to therapeutic dosing described earlier). Despite the limited evidence, it may be prudent to reduce acetaminophen dosage and duration of therapy for CHAPTER overdosed on enteric-coated or modified-release preparations of aspirin should be treated regardless of initial serum salicylate concentrations and be observed for approximately 24 hours with serial serum salicylate measurements until a declining level is confirmed. Salsalate overdoses may warrant an even longer period of observation. 38 Although the determination of serial salicylate concentrations offers valuable information regarding the effectiveness of the treatment implemented, it is not a substitute for clinical evaluation of a patient, and management decisions should not be solely based on a particular serum salicylate concentra tion. Early consultation with a clinical toxicologist or the regional poison control center is recommended. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec15_p1187-1332.indd 1252 8/2/19 8:39 PM

sions should not be solely based on a particular serum salicylate concentra tion. Early consultation with a clinical toxicologist or the regional poison control center is recommended. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec15_p1187-1332.indd 1252 8/2/19 8:39 PM CHAPTER 190: Acetaminophen 1253  IV ACETAMINOPHEN The recommended dosing of IV acetaminophen for adults or chil dren weighing more than 50 kg is 650 milligrams every 4 hours or 1000 milligrams every 6 hours, with a maximum total daily dose of 4 grams. For adults or children weighing less than 50 kg, the re commended dosing is 12.5 milligrams/kg every 4 hours or 15 milligrams/kg every 6 hours (maximum individual dose of 750 milligrams), with a maximum total daily dose of 75 milligrams/kg or 3750 milligrams, whichever is less. Peak concentrations following IV administration occur at the end of the 15-minute infusion period. 13 Compared to a similar dose of oral acetaminophen, IV acetaminophen achieves a 70% greater maximum concentration but provides a similar total drug exposure.  ACETAMINOPHEN METABOLISM Acetaminophen metabolism after therapeutic ingestion is primarily by glucuronidation and sulfation (Figure 190-1). In overdose, normal pathways for acetaminophen metabolism are saturated and a larger proportion is oxidized by the CYP450 system to this population. In contrast, children, because of their greater abil ity to metabolize acetaminophen through hepatic sulfation, may be at decreased risk for developing hepatotoxicity following a moderate overdose. 7-9 After ingestion of therapeutic doses, acetaminophen is rapidly absorbed from the GI tract, and peak serum concentrations are usually achieved within 30 minutes to 2 hours. Following an overdose, peak serum concentrations are usually achieved within 2 hours. Delayed absorption can occur especially after overdose of acetaminophen preparations combined with opioid or antimuscarinic medications, as well as those with altered-release kinetics such as extended-release preparations. 10-12 In therapeutic amounts, acetaminophen has nearly 100% bioavailability, is approximately 20% bound to serum proteins, has a volume of distribution around 0.85 L/kg, and has an elimination half-life of approximately 2.5 hours. The therapeutic concentration for the antipyretic effect of acetaminophen is between 10 and 20 micrograms/mL (66 to 132 micromole/L), but therapeutic concentrations for an algesia are not established. Oral acetaminophen appears to be nontoxic when administered following therapeutic dosing guidelines. O Glucuronide Renal Excretion Renal Excretion N-acetyl-p-benzoquinoneimine (NAPQI) NAPQI APAP-mercaptateA (40%–67%) UDP-glucuronosyltransferase (20%–46%) Phenolsulfotransferase Glutathione Glutathione-Stransferase Cytochrome P450 Cytochrome P450 APAP-mercaptateB If Glutathione <30% normal SP rotein Cell death Covalent binding of amino acids in proteins and enzymes Acetaminophen Acetaminophen (<5%) (5%–15%) CC H3 HN CC H3 OH SO4 CC H3 CC H3 CC H3 CC H3 CC H3 N CC H3 CC H3 FIGURE 190-1. Acetaminophen metabolism. A. After ingestion of therapeutic amounts, predominant metabolism is via glucuronidation and sulfation. The small amount of N-acetylp-benzoquinoneimine (NAPQI) generated is conjugated with glutathione to a nontoxic compound. B. After ingestion of large amounts, glucuronidation and sulfation are saturated, and an increased amount of NAPQI is generated. Detoxification of NAPQI to a nontoxic compound soon depletes glutathione stores, leaving excess NAPQI to bind to intracellular proteins, causing cell death. APAP = N-acetyl-p-aminophenol (acetaminophen). Tintinalli_Sec15_p1187-1332.indd 1253 8/2/19 8:39 PM

n are saturated, and an increased amount of NAPQI is generated. Detoxification of NAPQI to a nontoxic compound soon depletes glutathione stores, leaving excess NAPQI to bind to intracellular proteins, causing cell death. APAP = N-acetyl-p-aminophenol (acetaminophen). Tintinalli_Sec15_p1187-1332.indd 1253 8/2/19 8:39 PM 1254 SECTION 15: Toxicology TABLE 190-1 Clinical Stages of Acute Acetaminophen Toxicity Stage 1 Stage 2 Stage 3 Stage 4 Approximate timing First 24 h Days 2–3 Days 3–4 After day 5 Clinical manifestations Anorexia Nausea Vomiting Malaise Improvement in anorexia, nausea, and vomiting Abdominal pain Hepatic tenderness Recurrence of anorexia, nausea, and vomiting Encephalopathy Anuria Jaundice Clinical improvement and recovery (7–8 d) Deterioration to multiorgan failure and death Laboratory abnormalities Elevated serum transaminases Elevated bilirubin and prolonged prothrombin time if severe Hepatic failure Metabolic acidosis Coagulopathy Renal failure Pancreatitis Improvement and resolution Continued deterioration a reactive metabolite, N-acetyl-p-benzoquioneimine (NAPQI). NAPQI is detoxified by hepatic glutathione to a nontoxic compound that can be renally eliminated. However, when hepatic stores of glutathione decrease to <30% of normal in the setting of overdose, NAPQI binds to hepatic macromolecules, resulting in a centrilobular hepatic necrosis. Observed hepatocyte damage typically progresses with cell lysis on the second day after an acute toxic exposure, releasing hepatic enzymes (such as transaminases) and NAPQI-hepatic protein adducts into the circulation where they are detectable in the serum. This corresponds generally to the development of overt clinical toxicity. CLINICAL FEATURES  FOUR STAGES OF ACETAMINOPHEN TOXICITY The clinical presentation of human acetaminophen poisoning can be roughly divided into four stages (Table 190-1). During the first 24 hours after exposure (stage 1), patients may be asymptomatic or have minimal and nonspecific clinical effects of toxicity, such as anorexia, nausea, vomiting, and malaise. By days 2 to 3 (stage 2), findings seen in stage 1 often improve, but clinical signs of hepatotoxicity (including right upper quadrant pain and tenderness) may occur and serum transaminases may be elevated. Even without treatment, most patients with mild to moderate hepatotoxicity recover without sequelae. However, by days 3 to 4 (stage 3), some patients will progress to fulminant hepatic failure. 14,15 Characteristic stage 3 findings include metabolic acidosis, coagulopathy, renal failure, encephalopathy, and recurrent GI symptoms. Patients who survive the complications of fulminant hepatic failure begin to recover over the next 2 weeks (stage 4), with complete resolution of hepatic dysfunction in survivors after 1 to 3 months. Acetaminophen may also cause acute, extrahepatic toxic effects, pre sumably because of the presence of CYP450 or similar enzymes (e.g., prostaglandin H synthase) in other organs. In rare cases, isolated renal injury, cardiac toxicity, and pancreatitis may occur. 16,17 Ingestion of massive doses of acetaminophen (e.g., >500 milligrams/kg or peak plasma acetaminophen concentration >750 micrograms/mL or >5000 micromole/L) can cause early-onset metabolic acidosis with an elevated lactate and altered sensorium even in the absence of either liver failure or hypotension.

s may occur. 16,17 Ingestion of massive doses of acetaminophen (e.g., >500 milligrams/kg or peak plasma acetaminophen concentration >750 micrograms/mL or >5000 micromole/L) can cause early-onset metabolic acidosis with an elevated lactate and altered sensorium even in the absence of either liver failure or hypotension. Likely mechanisms for this finding include depletion of liver glutathione stores resulting in generation of 5- ox oproline and metabolite-induced inhibition of mitochondrial respiration.18,19 DIAGNOSIS A toxic exposure to acetaminophen is suggested when a patient ≥6 years old ingests (1) >10 grams or 200 milligrams/kg as a single ingestion, (2) >10 grams or 200 milligrams/kg over a 24-hour period, or (3) >6 grams or 150 milligrams/kg per 24-hour period for at least 2 consecutive days. For children <6 years old, ingestion of 200 milligrams/kg or more of acetaminophen as a single ingestion or over an 8-hour period, or of 150 milligrams/kg per 24-hour period for the preceding 48 hours is considered a toxic exposure. These values are empiric and not validated in human trials, but they are widely used as recommendations for emergency evaluation. Due to the widespread availability of acetaminophen-containing products, limited accuracy of the medical history, the delayed nature of clinical manifestations after overdose, and the serious complications of acute toxicity without antidotal therapy, measurement of a serum acetaminophen concentration is recommended for all patients presenting to the ED with an intentional overdose .20,21 Potentially toxic acetaminophen concentrations are occasionally identified in patients who overdose but deny ingesting acetaminophen. 22,23 Therefore, empirical testing of all patients with presumed intentional or chronic acetaminophen overdose may be cost-effective, as the estimated cost of treating a single patient for complications of acetaminophen-induced hepatotoxicity is judged to outweigh the cost of routine laboratory testing all intentional overdose patients.  THE RUMACK-MATTHEW NOMOGRAM The implication of a measured acetaminophen concentration is determined by plotting the value on the Rumack-Matthew nomogram (Figure 190-2). 24 This nomogram was derived from a retrospective analysis of oral acetaminophen overdose patients and their clinical outcomes. The original nomogram line separating possible toxicity from unlikely toxicity was based on a 4-hour acetaminophen concentration of 200 micrograms/mL (1300 micromole/L), but was subsequently modified by moving the line to a 4-hour acetaminophen concentra tion of 150 micrograms/mL (1000 micromole/L) to increase the safety margin for treatment decisions. The nomogram only directly applies to an acetaminophen concentration obtained after a single oral exposure and during the window between 4 hours and 24 hours after ingestion. Outcome prediction using this nomogram cannot be applied to acetaminophen concentrations obtained outside this window or following chronic or recurrent exposures. Obtaining multiple acet aminophen concentrations following acute overdose is rarely indicated in the absence of hepatotoxicity. 25,26 An initial concentration below the nomogram line may rarely “cross the line” in patients who ingest acetaminophen preparations known to have prolonged absorption kinetics. 12 However, the clinical significance of “crossing the line” in this fashion is unknown. Similarly, because the nomogram was constructed and verified by using only a single serum concentration, the clinical implications of a concentration above the line that falls below it on repeat analysis are unknown.

tion kinetics. 12 However, the clinical significance of “crossing the line” in this fashion is unknown. Similarly, because the nomogram was constructed and verified by using only a single serum concentration, the clinical implications of a concentration above the line that falls below it on repeat analysis are unknown. Based on data obtained before the widespread use of antidotal therapy, patients with serum acetaminophen concentrations above the original line (4-hour postingestion concentration >200 micrograms/mL or >1300 micromole/L) were observed to have a 60% risk of dev eloping hepatotoxicity (defined as alanine aminotransferase >1000 IU/mL), a 1% risk of renal failure, and a 5% risk of mortality. 27 In addition, patients with extremely high serum acetaminophen concentrations (above a parallel line coinciding with a 4-hour postingestion concentration of Tintinalli_Sec15_p1187-1332.indd 1254 8/2/19 8:39 PM

y (defined as alanine aminotransferase >1000 IU/mL), a 1% risk of renal failure, and a 5% risk of mortality. 27 In addition, patients with extremely high serum acetaminophen concentrations (above a parallel line coinciding with a 4-hour postingestion concentration of Tintinalli_Sec15_p1187-1332.indd 1254 8/2/19 8:39 PM CHAPTER 190: Acetaminophen 1255 300 micrograms/mL or 2000 micromole/L) were observed to have a 90% risk of developing hepatotoxicity. The prediction of a safe out come below the nomogram line corresponding to a 4-hour postingestion concentration of 150 micrograms/mL (1000 micromole/L) was confirmed in patients who did not receive antidotal therapy; the incidence of hepatotoxicity in patients with acetaminophen concentrations below this nomogram line was 1%, and all patients recovered without complications. A validated method to determine potential toxicity from IV acetaminophen overdose has not been established. Fortunately, the European experience with IV acetaminophen suggests that these over doses appear to be rare in-hospital occurrences that are likely to occur following an error in calculating the acetaminophen dose in pediatric patients. 28-30 The available clinical data for evaluating IV acetamino phen overdose remain limited to several published case reports. 28,30,31 Based on these data, the United Kingdom published revised precau tionary guidelines recommending empiric acetylcysteine for any single IV acetaminophen dose above 60 milligrams/kg or acetaminophen concentrations above 50 micrograms/mL on the nomogram at 4 hours. The Rumack-Matthew nomogram was, however, derived solely from oral acetaminophen overdose patients, and the effectiveness of application to determine toxicity following IV acetaminophen overdose is unknown. TREATMENT  GI DECONTAMINATION For most cases of acetaminophen poisoning, adequate GI decontamination consists of the early administration of activated charcoal orally or through a nasogastric tube. 32,33 More aggressive forms of decontamina tion, such as gastric lavage or whole-bowel irrigation, are unnecessary because of the rapid GI absorption of acetaminophen and the reliable success of treating acetaminophen poisoning with acetylcysteine.  ACETYLCYSTEINE The mainstay for the prevention or treatment of acetaminophen toxicity is the administration of acetylcysteine. 34-36 The current “ standard” acetylcysteine protocols were developed primarily from Take level at least 4 hours after ingestion Recommend treatment if level is above broken line Toxicity Unlikely Possible Toxicity 42 6242016 Hours after ingestion Acetaminophen plasma concentration micrograms/mL micromole/L FIGURE 190-2. Rumack-Matthew nomogram. Tintinalli_Sec15_p1187-1332.indd 1255 8/2/19 8:39 PM

from Take level at least 4 hours after ingestion Recommend treatment if level is above broken line Toxicity Unlikely Possible Toxicity 42 6242016 Hours after ingestion Acetaminophen plasma concentration micrograms/mL micromole/L FIGURE 190-2. Rumack-Matthew nomogram. Tintinalli_Sec15_p1187-1332.indd 1255 8/2/19 8:39 PM 1256 SECTION 15: Toxicology observational trials, and it is not clear if they represent the most eff ective regimens.37 Although its mechanisms of action are not fully understood, acetylcysteine is thought to have two important beneficial effects. 36,37 In early acetaminophen poisoning (<8 hours after ingestion), acetyl cysteine 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. 27 The longer the initiation of acetylcysteine therapy is delayed beyond 8 hours after ingestion, the greater is the risk of devel oping hepatotoxicity.38 Even if administration is delayed up to 24 hours, acetylcysteine reduces risk of hepatotoxicity compared to historical controls. 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 treat ing a pregnant patient following an acetaminophen overdose should remain the same. Acetylcysteine treatment has never been associated with fetal malformations in humans, but fetal demise and malformations have been described following a delay in acetylcysteine treatment after acetaminophen overdose in first-trimester pregnant women. IV Acetylcysteine IV acetylcysteine has supplanted oral administra tion due to its greater ease of administration, greater patient acceptance, equivalent efficacy, and shorter duration of treatment for many cases of acetaminophen poisoning. 40-43 The major limitation of IV acetylcysteine is the occurrence of drug-related anaphylactoid reactions, which occur in 4% to 17% of patients (most during the first 2 hours of admini stration). 44,45 Mild cases are treated with diphenhydramine, and severe cases are treated by temporarily slowing or stopping the acetylcysteine infusion. Unfortunately, fulminant liver failure requir ing transplant has occurred after discontinuation of N-acetylcysteine due to anaphylactoid reaction. 4,46 IV N-acetylcysteine infusion can be reinitiated at a slower rate after administration of diphenhydramine in asymptomatic patients. 47 Asthmatics appear to have a greater risk of anaphylactoid reactions during IV acetylcysteine therapy, whereas high acetaminophen concentrations are protective from developing anaphylactoid reactions.

steine infusion can be reinitiated at a slower rate after administration of diphenhydramine in asymptomatic patients. 47 Asthmatics appear to have a greater risk of anaphylactoid reactions during IV acetylcysteine therapy, whereas high acetaminophen concentrations are protective from developing anaphylactoid reactions. 45,46,48-50 The standard regimen for IV acetylcysteine uses a 21-hour protocol including a loading dose of 150 milligrams/kg over 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). 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 regi mens are being explored. 51-55 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.56 Given the volume and hypotonicity of fluid required, specific acetylcysteine weight-based fluid volume guidelines should be followed for children and small adults (<40 kg), and these patients should be carefully monitored to avoid fluid overload and hyponatremia during treatment. A dose calculator and detailed pediatric dilution directions for IV acetylcysteine are available at Acetadote.com. 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. 42,57-60 IV acetylcysteine is the route of choice for patients with acetaminophen-induced fulminant hepatic failure because oral acetyl cysteine has not been adequately studied in this setting. 61 Oral Acetylcysteine The standard 72-hour oral acetylcysteine reg imen 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. TABLE 190-2 Acetylcysteine Dosing Regimens PO IV Adult IV Pediatric (21–40 kg) IV Pediatric (5–20 kg) Preparation Available as 10% and 20% solutions. Dilute to 5% solution for PO administration. Available as 20% solution. Dilution required. Available as 20% solution. Dilution required. Available as 20% solution. Dilution required. Loading dose 140 milligrams/kg 150 milligrams/kg in 200 mL 5% dextrose in water infused over 60 min 150 milligrams/kg in 100 mL 5% dextrose in water infused over 60 min 150 milligrams/kg in 3 mL/kg 5% dextrose in water infused over 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) followed by 100 milligrams/kg in 1000 mL 5% dextrose in water infused over 16 h (6.25 milligrams/kg per hour) 50 milligrams/kg in 250 mL 5% dextrose in water infused over 4 h (12.5 milligrams/ kg per hour) followed by 100 milligrams/kg in 500 mL 5% dextrose in water infused over 16 h (6.25 milligrams/kg per hour) 50 milligrams/kg in 7 mL/kg 5% dextrose in water infused over 4 h (12.5 milligrams/kg per hour) followed by 100 milligrams/kg in 14 mL/kg 5% dextrose in water infused over 16 h (6.25 milligrams/kg per hour) Duration of therapy 72 h* 21 h* 21 h 21 h Comments Dilute with powdered drink mix, juice, or soda. Serve chilled. Drink through a straw to reduce disagreeable smell.

used over 4 h (12.5 milligrams/kg per hour) followed by 100 milligrams/kg in 14 mL/kg 5% dextrose in water infused over 16 h (6.25 milligrams/kg per hour) Duration of therapy 72 h* 21 h* 21 h 21 h Comments Dilute with powdered drink mix, juice, or soda. Serve chilled. 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. Monitor for drug-related adverse effects and anaphylactoid reactions. *Check with your institution or poison control center for alternative dosing protocols and for management of adverse effects. Tintinalli_Sec15_p1187-1332.indd 1256 8/2/19 8:39 PM

. Monitor for drug-related adverse effects and anaphylactoid reactions. Monitor for drug-related adverse effects and anaphylactoid reactions. *Check with your institution or poison control center for alternative dosing protocols and for management of adverse effects. Tintinalli_Sec15_p1187-1332.indd 1256 8/2/19 8:39 PM CHAPTER 190: Acetaminophen 1257  EXTRACORPOREAL ELIMINATION Recent guidelines recommend extracorporeal treatment (extracorporeal membrane oxygenation) in addition to acetylcysteine only in the setting of altered mental status, metabolic acidosis, an elevated lactate, and an acetaminophen level of >900 milligrams/L. In all other instances, extra corporeal treatment would only be recommended in the rare clinical scenario where acetylcysteine was unavailable or could not be administered. 62 Acetylcysteine is dialyzable, and a dose increase to account for acetylcysteine removal during hemodialysis (50%) or continuous renal replacement therapy (25%) is recommended. 63,64  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 pre sentation ( Figure 190-3). 25 The risk of hepatotoxicity increases with the lag time between ingestion and initiation of acetylcysteine therapy.38 The optimal outcome with acetylcysteine therapy is achieved when it is administered within 8 hours after ingestion, so the optimal “decisiontime window” for treatment is between the 4-hour acetaminophen concentration measurement and 8-hour goal to initiate acetylcysteine. No further acetaminophen serum measurements are necessary once the need for acetylcysteine therapy has been determined until the comple tion of the course of therapy. Presentation Within 4 Hours of Ingestion For patients who present to the ED within 4 hours and are likely to 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 the acetaminophen concentration within the 8-hour postingestion window, 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 after ingestion, empirically initiate acetylcysteine therapy, by either route, 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 pos sible. GI decontamination may be performed, particularly for suspected co-ingestants, but it may have limited effectiveness because of the delay in presentation. If the laboratory can determine the acetaminophen concentration within 8 hours after ingestion, 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 inges tion 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.

s tion 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 micromole/L) suggests that the patient may be at risk for develop ing hepatotoxicity. Similarly, elevated serum transaminases suggest <4 h from ingestion Between 4 and 24 h from ingestion Unknown or >24 h from ingestion APAP Ingestion Consider GI decontamination Send >4 h APAP level Level available <8 h Level not available until >8 h Plot on nomogram Give 1st dose AC (within 8 h) Toxic: AC Rx Not toxic: symptomatic Rx Consider GI decontamination for unknown ingestion Send APAP levels Send LFTs (AST, ALT, PT) Give 1st dose AC APAP >10 micrograms/mL or AST/ALT increased Y es: Continue AC pH <7 .3 PT >100 Cr >3.3 AMS Refer to liver transplant unit No: Supportive Rx FIGURE 190-3. Treatment guidelines for acetaminophen (APAP) ingestion. All times noted are after ingestion. AC = acetylcysteine; ALT = alanine aminotransferase; AMS = altered mental status; AST = aspartate aminotransferase; Cr = creatinine; LFTs = liver function tests; PT = prothrombin time; Rx = treatment. Tintinalli_Sec15_p1187-1332.indd 1257 8/2/19 8:39 PM

etaminophen (APAP) ingestion. All times noted are after ingestion. AC = acetylcysteine; ALT = alanine aminotransferase; AMS = altered mental status; AST = aspartate aminotransferase; Cr = creatinine; LFTs = liver function tests; PT = prothrombin time; Rx = treatment. Tintinalli_Sec15_p1187-1332.indd 1257 8/2/19 8:39 PM 1258 SECTION 15: Toxicology the possibility of ongoing hepatic toxicity. Therefore, continued ace tylcysteine therapy is indicated if the acetaminophen concentration is measurable or if the serum transaminases are elevated. If serum acet aminophen concentration is <10 micrograms/mL (<66 micromole/L) and the serum transaminases are not elevated, the acetylcysteine can be discontinued. DISPOSITION AND FOLLOW-UP Recheck serum acetaminophen and transaminase levels at the completion of acetylcysteine therapy with continuation of acety lcysteine infusion at the rate of 6.25 milligrams/kg per hour. If serum acetaminophen concentration is not detectable or is <10 micrograms/mL (66 micromole/L) and transaminase concentrations are normal, the acetylcysteine therapy can be discontinued. 37,43 If either the serum acetaminophen concentration or liver function tests are elevated, the acetylcysteine should be continued until the serum acetaminophen concentration is undetectable and the patient has demonstrated clearly downtrending transaminases (at least two values) and there are no signs of synthetic liver dysfunction. All patients requiring acetylcysteine therapy should be admitted to the hospital until the completion of the therapy. In general, admission to a hospital floor bed is adequate unless the co-ingestant is of concern, hepatotoxicity is severe, or the patient is suicidal and 24-hour direct observation cannot be arranged. Patients who are not at risk for devel oping acetaminophen-induced hepatotoxicity (e.g., acetaminophen concentration below the nomogram or unmeasurable acetaminophen concentration with normal hepatic transaminase concentrations) should be observed in the ED for 4 to 6 hours to exclude potentially toxic co-ingestants before disposition. Psychiatric evaluation should be con sidered for patients with intentional acetaminophen overdoses. Cases of acetaminophen ingestion or toxicity should be reported to the regional poison control center for both data collection purposes and assistance with management. SPECIAL CONSIDERATIONS  FULMINANT HEPATIC FAILURE Unfortunately, a small percentage of patients who overdose with acet aminophen will develop fulminant hepatic failure. The mortality rate for patients with acetaminophen-induced fulminant hepatic failure without acetylcysteine therapy is significant. Most fatalities occur on days 3 to 5 after overdose and are attributed to hepatic complications such as cerebral edema, hemorrhage, shock, acute lung injury, sepsis, and mul tiorgan failure. Patients who survive fulminant hepatic failure generally begin to show evidence of recovery by days 5 to 7. Survivors will even tually develop complete hepatic regeneration without any per sistence of hepatic impairment.

ions such as cerebral edema, hemorrhage, shock, acute lung injury, sepsis, and mul tiorgan failure. Patients who survive fulminant hepatic failure generally begin to show evidence of recovery by days 5 to 7. Survivors will even tually develop complete hepatic regeneration without any per sistence of hepatic impairment. Acetylcysteine treatment decreases the incidence of cerebral edema, reduces vasopressor requirements, and improves survival in acetaminophen-induced fulminant hepatic failure.61,65 Acetylcysteine also appears to be beneficial in the treatment of other forms of hepatic failure, including viral hepatitis and alcoholic cirrhosis.66-68 Prognostic indicators (aka King’s College Criteria) associated with the highest risk of mortality from acetaminophen-induced fulminant hepatic failure include metabolic acidosis (arterial pH <7.30) despite fluid and hemodynamic resuscitation, or a combination of coagulopathy (prothrombin time >100 seconds), renal insufficiency (serum creatinine >3.3 milligrams/dL or >292 micromole/L), and grade III or IV hepatic encephalopathy. 69 Other predictors of a poor prognosis individually include an Acute Physiology and Chronic Health Evaluation II score >15, elevated serum lactate (>26 milligrams/dL or >3.0 mmol/L) after fluid resuscitation, hypoglycemia, and elevated serum phosphate (>3.71 milligrams/dL or >1.2 mmol/L) on the second day after ingestion. 70-73 Treatment for acetaminophen-induced fulminant hepatic fail ure includes acetylcysteine therapy; correction of coagulopathy and acidosis; monitoring for and aggressive treatment of cerebral edema, hypoglycemia, and electrolyte abnormalities; and early patient referral to a liver specialty or transplant center. Unlike the treatment of early acet aminophen toxicity, IV acetylcysteine therapy should be continued past the 21-hour standard regimen and until the patient recovers, receives a liver transplant, or dies.  MULTIPLE-DOSE AND EXTENDED-RELEASE ACETAMINOPHEN INGESTIONS Patients with staggered acetaminophen ingestions and liver injury often have delayed presentation to the hospital and a higher rate of adverse outcomes. 74 Multiple closely spaced acetaminophen ingestions and extended-release acetaminophen ingestions represent two unique aspects of acetaminophen poisoning for which the Rumack-Matthew nomogram cannot be applied because a single time of ingestion does not exist. A conservative approach is to assume that a single ingestion occurred at the earliest possible time stated by the patient, with the acetaminophen concentration plotted on the Rumack-Matthew nomogram based on this artificial time and treatment decisions made accordingly. For example, if the patient ingests five doses of 50 milligrams/kg of acetaminophen over a 4-hour period beginning 8 hours ago, a single acetaminophen ingestion is assumed to have occurred 8 hours ago, and the serum concentration is accordingly plotted on the nomogram. Extended-release acetaminophen formulations consist of a bilay ered tablet containing a 325-milligram immediate-release outer layer and a 325-milligram slow, continuous-release, highly compressed inner layer. Because there are few clinical data concerning overdose with these preparations, treatment guidelines remain conservative, and the manufacturer recommends obtaining a second acetaminophen concentration 4 to 6 hours after the first concentration in those situations in which the first measured concentration (4 to 8 hours after ingestion) is elevated, but below the nomogram line. 10,75,76 A full course of acetyl cysteine therapy should be instituted (or continued if already started) if the second acetaminophen concentration is above the nomogram line.

centration in those situations in which the first measured concentration (4 to 8 hours after ingestion) is elevated, but below the nomogram line. 10,75,76 A full course of acetyl cysteine therapy should be instituted (or continued if already started) if the second acetaminophen concentration is above the nomogram line. If the initial concentration is above the nomogram line, standard therapy should be administered, and there is no need to obtain a second concentration.  MASSIVE ACETAMINOPHEN OVERDOSE Patients presenting after massive (>40 grams or 500 milligrams/kg) acetaminophen overdose are at high risk of hepatotoxicity, even with early acetylcysteine administration. 63,77-79 The standard 21-hour proto col relies on empiric dosing, and this model may prove inadequate for patients with massive acetaminophen overdose. At this time, no data demonstrate superiority of an alternative regimen, but in patients with massive acetaminophen overdose, enhanced therapeutic measures should be considered. Options include the addition of oral acetylcys teine to the standard IV protocol, increasing the third infusion dose to 200 milligrams/kg over 16 hours as opposed to the dose of 100 mil ligrams/kg over 16 hours used in the standard IV acetylcysteine proto col, or reloading the standard acetylcysteine regimen at completion of the 21-hour protocol if serum acetaminophen concentration remains significantly elevated. 80,81  IV ACETAMINOPHEN OVERDOSE Accepted guidelines for treatment of IV acetaminophen overdose do not currently exist in the United States. The United Kingdom has published revised precautionary guidelines recommending empiric acetylcysteine for any single IV acetaminophen dose >60 milligrams/kg or acetaminophen concentrations >50 micrograms/mL on the nomogram at 4 hours. The local poison center should be contacted for guidance following any suspected IV acetaminophen overdose. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec15_p1187-1332.indd 1258 8/2/19 8:39 PM