Acetaminophen Paracetamol Poisoning in Adults- Treatment

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Acetaminophen (paracetamol) poisoning in adults: Treatment Authors: Kennon Heard, MD; Richard Dart, MD, PhD; Section Editor: Stephen J Traub, MD Deputy Editor: Jonathan Grayzel, MD, FAAEM Last literature review version 18.1: January 2010 | This topic last updated: November 4, 2009 INTRODUCTION — Acetaminophen (APAP) poisoning is among the most common causes of medication-related poisoning and death. Acetaminophen poisoning may occur following a single acute ingestion or through the repeated ingestion of supratherapeutic amounts. The management of the acetaminophen-poisoned patient may include stabilization, decontamination, and administration of acetylcysteine, a specific antidote. The duration of acetylcysteine treatment is determined by the type of ingestion and the presence or absence of elevated serum alanine aminotransferase (ALT) concentrations. The treatment of APAP poisoning is reviewed here. The diagnosis of APAP poisoning, both acute and chronic, and the management of hepatic injury or failure are discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis" and "Overview of the treatment of acute liver failure".) GENERAL MANAGEMENT — The initial management of acetaminophen poisoning is determined by the patient's presenting symptoms. Most patients who present early (within 24 hours) after an acute acetaminophen ingestion are asymptomatic, while others may require treatment for symptoms related to coingestants. As there are no early symptoms that predict acetaminophen toxicity, poisoning severity following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the Rumack-Matthew nomogram (graph 1). Use of the nomogram, as well as risk factors for hepatotoxicity and the diagnosis of both acute and chronic acetaminophen poisoning, are discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis".) Patients who present later may manifest symptoms and signs of hepatic injury or failure, such as nausea, vomiting, jaundice, abdominal pain, renal injury, coagulopathy (eg, gastrointestinal bleeding), hepatic encephalopathy, cerebral edema, or hypotension. These patients may require emergent resuscitation, including airway management, intravenous fluids, vasopressors, hemodialysis, or management of cerebral edema. (See "Overview of the treatment of acute liver failure".)

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Techniques used in the resuscitation of adults are discussed separately. (See "Basic airway management in adults" and "Advanced airway management in adults" and "Treatment of severe hypovolemia or hypovolemic shock in adults" and "Use of vasopressors and inotropes" and "Evaluation and management of elevated intracranial pressure in adults".) GI DECONTAMINATION — Patients who present soon after a potentially toxic ingestion of acetaminophen (single dose ≥7.5 g) are likely to benefit from gastrointestinal decontamination. We suggest treatment with activated charcoal (AC), 1 g/kg (maximum dose 50 g) by mouth in all patients who present within four hours of a known or suspected acetaminophen ingestion, unless there are contraindications to its administration. Charcoal should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving charcoal. Asymptomatic patients who present more than four hours after a reported ingestion are unlikely to benefit from AC, and we do not recommend routine treatment in these patients. A general approach to decontamination of poisoned patients is discussed separately. (See "Decontamination of poisoned adults".) A number of studies using simulated overdose models have shown that AC reduces acetaminophen exposure [1]. Several clinical trials have confirmed these findings: •

One randomized trial evaluating decontamination following acetaminophen overdose

found that patients treated with AC had a larger decrease in serum acetaminophen concentrations than those treated with gastric lavage or an emesis-inducing drug [2]. •

A prospective observational study found that patients who received AC prior to

acetylcysteine were less likely to develop liver injury than those who did not [3]. •

A retrospective study of 981 consecutive patients with an acute

acetaminophen overdose found that patients who received AC within two hours of ingestion were less likely to require acetylcysteine treatment [4]. •

Another retrospective study found that administration of AC to patients who

presented over four hours after acetaminophen ingestion was associated with lower peak alanine aminotransferase (ALT) concentrations, and that these effects were independent of the time of acetylcysteine administration. While limited, this study suggests that administration of AC more than two hours after ingestion may be beneficial [5]. Studies have shown that induced emesis [6,7] and gastric lavage [8,9] limit the absorption of acetaminophen after simulated overdose and in clinical trials [2,6]. However, these therapies appear to be less effective than activated charcoal, so they are not routinely recommended [2,4]. ANTIDOTE: ACETYLCYSTEINE Effectiveness of acetylcysteine — Acetylcysteine is the accepted antidote for acetaminophen poisoning and is given to all patients at significant risk for hepatotoxicity.

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Serious hepatotoxicity is uncommon and death extremely rare if acetylcysteine is administered within eight hours following acetaminophen overdose [10-12]. The key to effective treatment is to start therapy before the onset of alanine aminotransferase (ALT) elevation. This is accomplished by initiating treatment within eight hours of an acute ingestion. Determination of the risk for hepatotoxicity following either acute or chronic acetaminophen ingestion is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis", section on 'Diagnosis'.) Although some controversy persists regarding mechanism, most toxicologists believe acetylcysteine prevents acetaminophen-induced hepatic injury by restoring hepatic glutathione stores. There are no randomized, placebo-controlled trials evaluating the efficacy of acetylcysteine for the prevention of hepatic injury from acetaminophen poisoning (they were considered unethical). However, several studies have described an extremely low incidence of hepatotoxicity following early acetylcysteine administration [10-15]. When acetylcysteine is administered late following acetaminophen ingestion to patients with evidence of hepatic failure, it decreases mortality and improves hepatic and cerebral function [16-18]. Confusion exists about the appropriate route and duration of early acetylcysteine therapy following acute ingestion. The two most common protocols are the 20 hour intravenous (IV) protocol [15] and the 72 hour oral protocol [11]. We review these protocols immediately below. A discussion of how they are modified based upon clinical circumstances is discussed further on. (See 'Duration of treatment' below.) 20 hour IV protocol — The 20 hour intravenous (IV) protocol for acetylcysteine treatment has been used in the United Kingdom since the 1970s. The approved 20 hour IV dosing regime is complicated and is performed as follows: •

Administer an initial loading dose of 150 mg/kg IV over 15 to 60 minutes (we

recommend 60 minutes). •

Next, administer a dose of 50 mg/kg IV over four hours.

•

Finally, administer a 16 hour infusion at 6.25 mg/kg per hour IV.

This treatment protocol provides a total of 300 mg/kg over 20 to 21 hours [15]. The treatment period is often extended when patients have large ingestions or elevated serum transaminase activity. This is discussed below. (See 'Duration of treatment' below.) 72 hour oral protocol — The 72 hour oral (PO) dosing protocol for acetylcysteine treatment has been used successfully in the US for more than 30 years. It is performed as follows: •

Give a loading dose of 140 mg/kg PO.

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•

Next, give a dose of 70 mg/kg PO every four hours for a total of 17 doses.

The dose does not need to be adjusted if the patient has been treated with activated charcoal. The incidence of hepatotoxicity for patients treated within eight hours of ingestion is less than 10 percent, but increases to approximately 40 percent if treatment is delayed beyond 16 hours. In the largest study of oral acetylcysteine, no deaths occurred among patients treated before the onset of transaminase elevation [11]. There are several reports describing truncated oral protocols. The duration of treatment is discussed further below. (See 'Duration of treatment' below.) IV versus oral — There are no head-to-head trials comparing the 20 hour IV and the 72 hour oral treatment protocols in patients treated early after ingestion. The best available data suggest that both routes are effective and differences are minimal. In most patients, either the oral or IV route is acceptable. IV administration is favored for patients with any of the following: •

Vomiting

•

Contraindications to oral administration (ie, pancreatitis, bowel ileus or obstruction,

bowel injury) •

Hepatic failure

•

Patients who refuse oral administration

Patients with evidence of hepatic failure require IV therapy. (See 'Treatment in hepatic failure' below.) Adverse reactions — While dosing errors are common during IV acetylcysteine administration [19], significant adverse events stemming from such miscalculations are rare. Anaphylactoid reaction — Prospective studies suggest that between 10 and 20 percent of patients treated with IV acetylcysteine develop an anaphylactoid reaction [20,21]. However, most of these subjects are able to tolerate the infusion when it is restarted. Patients who experience only flushing do not require intervention and the infusion can be continued, unless more severe signs develop. Patients who develop urticaria or angioedema should have the infusion stopped and be treated with diphenhydramine (1 mg/kg IV up to 50 mg). The infusion can be restarted once symptoms resolve. Patients who develop hypotension or respiratory symptoms after IV acetylcysteine therapy will generally tolerate oral acetylcysteine. If the patient cannot be treated with oral acetylcysteine, the clinician should consult a medical toxicologist or poison control center for guidance. Before restarting an infusion in such cases, the patient should be pretreated with IV diphenhydramine (1 mg/kg up to 50 mg), cimetidine (5 mg/kg up to 300 mg), and oral ephedrine (0.5 mg/kg up to 25 mg) [22].

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Any patient who develops hypotension or respiratory symptoms should be monitored in an ICU setting with airway management capability, and epinephrine should be available to treat life-threatening reactions. There is no convincing evidence that a slower infusion decreases the risk of anaphylactoid reactions. Vomiting — Approximately 33 percent of subjects treated with oral acetylcysteine develop nausea and vomiting [23]. The palatability of acetylcysteine can be improved by diluting it to a 5 percent solution in cola or juice, covering the cup, and drinking through a straw. It is reasonable to administer an antiemetic to nauseated patients or patients who have vomited prior to giving oral acetylcysteine. Serotonin 5-HT3 receptor antagonists (eg, ondansetron) have been suggested as the antiemetics of choice [24]. If a patient vomits within 60 minutes of an oral dose of acetylcysteine, the dose should be repeated. Duration of treatment — While the efficacy of IV and oral administration is similar, controversy persists about the optimal duration of acetylcysteine therapy. The current treatment protocols approved by the US Food and Drug Administration are time-based (20 and 72 hours). While these protocols are adequate for the vast majority of patients, it is clear that the 72 hour protocol is longer than needed for most patients while the 20 hour protocol is not long enough for some others. Many authors recommend that therapy be tailored to each patient, using clinical endpoints rather than time to determine duration [25-28]. We suggest the following approach for three common clinical scenarios based upon the type of ingestion and the clinical status of the patient: •

Acute ingestion with treatment started when ALT is NOT elevated or within eight

hours of ingestion - Administer IV or oral acetylcysteine for a minimum of 20 hours (some authors suggest longer treatment when the oral route is used) [29]. Check the serum ALT and acetaminophen concentrations as the patient is approaching the end of the protocol (approximately 18 hours after starting treatment). If the serum ALT is elevated OR if the serum acetaminophen concentration is detectable, continue treatment with acetylcysteine at 6.25 mg/kg per hour and obtain a serum acetaminophen concentration and ALT measurement every 12 hours thereafter. If the ALT is elevated, also measure the international normalized ratio (INR). Treatment can be stopped when the serum acetaminophen concentration is undetectable, the ALT is clearly decreasing or in the normal range, and the INR is less than two. There is no uniformly accepted definition of "clearly decreasing." One conservative definition is a decrease of more than 50 percent from the peak measurement or three consecutive decreasing values, all below 1000 IU/L.

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•

Repeated ingestion with treatment started when ALT is NOT elevated - Administer IV

or oral acetylcysteine for a minimum of 12 hours [30]. After 11 hours of treatment check the serum ALT activity and acetaminophen concentration. If the serum ALT is elevated OR if the serum acetaminophen concentration is detectable, continue treatment with acetylcysteine at 6.25 mg/kg per hour and obtain a serum acetaminophen concentration and ALT measurement every 12 hours thereafter. If the ALT is elevated, also measure the patient's INR. Treatment can be stopped when the serum acetaminophen concentration is undetectable, the ALT is clearly decreasing or in the normal range, and the INR is less than two. There is no uniformly accepted definition of "clearly decreasing." One conservative definition is a decrease of more than 50 percent from the peak measurement or three consecutive decreasing values, all below 1000 IU/L. •

Evidence of hepatic injury following either acute or repeated ingestion - Administer

IV or oral acetylcysteine until the ALT is clearly decreasing, the INR is less than two, AND the serum acetaminophen concentration is undetectable. There is no uniformly accepted definition of "clearly decreasing." One conservative definition is a decrease of more than 50 percent from the peak measurement or three consecutive decreasing values, all below 1000 IU/L. Patients who develop hepatic encephalopathy are treated as described immediately below. Treatment in hepatic failure — If a patient develops hepatic failure (hepatic failure is differentiated from hepatic injury by the onset of encephalopathy), IV acetylcysteine decreases mortality and improves hepatic microcirculatory function. There are no studies of oral acetylcysteine in hepatic failure, so all patients should receive IV therapy. The dosing protocol is the same as the 20 hour regimen used for the prevention of hepatic injury, except the final infusion rate (6.25 mg/kg per hour) is continued until the patient receives a liver transplant OR the hepatic encephalopathy resolves [2,6,16] and the INR is less than two [31]. Additional supportive therapies for patients with acute hepatic failure are started as indicated. (See "Overview of the treatment of acute liver failure".) Monitoring during treatment — If acetylcysteine therapy is initiated within eight hours of ingestion (ie, before ALT elevation), one major guideline recommends no additional testing at the end of treatment [32]. However, we suggest measuring the ALT prior to stopping acetylcysteine and continuing treatment if the ALT is abnormal, as some patients will develop liver injury during the treatment period. We also suggest remeasuring the serum acetaminophen concentration prior to stopping acetylcysteine to verify that the level is undetectable. Our approach is based upon a few case reports where patients had toxic acetaminophen concentrations at the end of the 20 hour IV treatment protocol [25-27].

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Other guidelines recommend measuring serum acetaminophen, international normalized ratio (INR), serum bicarbonate, and serum creatinine at the end of treatment and continuing treatment if any value is abnormal [33]. The ALT is used to monitor the degree of hepatic injury and the other tests are used to determine the need for liver transplant [34]. We suggest measuring the ALT and INR every 12 hours for any patient who develops ALT elevation. More frequent testing does not allow enough time to detect clinically meaningful trends. If the patient develops an ALT greater than 1000 IU/L, coagulopathy (ie, INR >1.5), or encephalopathy, then the serum bicarbonate, glucose, and creatinine should also be measured every 12 hours. Closer monitoring (eg, ICU admission, cardiac monitor) may be indicated based upon the patient's clinical condition if a significant coingestion is known or suspected or other problems arise. Side effects — Both therapeutic serum concentrations of acetylcysteine and high concentrations of acetaminophen can elevate the INR. These elevations are usually mild (INR should not be greater than 1.5), occur between 4 and 20 hours post ingestion, and resolve as treatment is continued [35]. OTHER TREATMENTS Cimetidine and other medications — Several other treatments have been suggested as possible adjuncts for the prevention of acetaminophen-induced liver injury. The most commonly cited is cimetidine, an inhibitor of acetaminophen metabolism [36-40]. While this treatment was useful in animal models, it had no effect in a clinical trial where patients were treated with acetylcysteine [41]. Other substances have also been evaluated in animal models, but none is considered standard care in humans [42-45]. Older studies evaluated therapies such as methionine, cysteamine, and dimercaprol [13,46,47], but these treatments were limited by adverse effects and play no role in current management. Indications for extracorporeal removal — Although acetaminophen is cleared by hemodialysis [48,49], the safety and efficacy of acetylcysteine leaves no role for dialysis in the management of acetaminophen poisoning if acetylcysteine is available. Extracorporeal removal may be useful for lowering serum acetaminophen concentrations if acetylcysteine is not available, but there are no systematic studies to evaluate the effectiveness of this treatment. Hemodialysis should never be considered an alternative to acetylcysteine therapy. ADDITIONAL RESOURCES — The management of acetaminophen toxicity can sometimes be complex and clinicians can benefit from expert guidance. To obtain emergent consultation with a medical toxicologist, call the United States Poison Control Network at 1800-222-1222

1-800-222-1222

, or access the World Health Organization's list

of international poison centers (www.who.int/ipcs/poisons/centre/directory/en). SUMMARY AND RECOMMENDATIONS

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•

The initial management of acetaminophen poisoning is determined by the patient's

presenting symptoms. Patients who present within 24 hours after an acute ingestion are generally asymptomatic. Patients who present later may manifest symptoms and signs of hepatic injury. There are no early symptoms that predict acetaminophen toxicity; poisoning severity in acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the Rumack-Matthew nomogram (graph 1). Risk factors for hepatotoxicity following acetaminophen ingestion, the diagnosis of acetaminophen ingestion, and the use of the nomogram are discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis".) •

Patients who present soon after a potentially toxic ingestion of

acetaminophen (single dose ≥7.5 g) are likely to benefit from gastrointestinal decontamination. We suggest treatment with activated charcoal, 1 g/kg (maximum dose 50 g) by mouth in all patients who present within four hours of a known or suspected acetaminophen ingestion, unless there are contraindications to its administration (Grade 2B). (See 'GI decontamination' above.) •

We recommend treatment with acetylcysteine for all patients with

acetaminophen poisoning at significant risk for hepatotoxicity (Grade 1A). The key to effective treatment is to start therapy before the onset of alanine aminotransferase (ALT) elevation. This is accomplished by initiating treatment within eight hours of an acute ingestion. Determination of the risk for hepatotoxicity following either acute or chronic acetaminophen ingestion is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis", section on 'Diagnosis'.) •

Acetylcysteine may be given intravenously (IV), using a 20 hour protocol, or orally,

using a 72 hour protocol. Each protocol and its indications are described in the text. (See '20 hour IV protocol' above and '72 hour oral protocol' above and 'IV versus oral' above.) •

IV administration of acetylcysteine is favored for patients who present acutely

following an ingestion and have any of the following: •

- Vomiting

•

- Contraindications to oral administration (ie, pancreatitis, bowel ileus or obstruction,

bowel injury) •

- Patients who refuse oral administration

In addition, patients with evidence of hepatic failure require IV therapy. •

We tailor acetylcysteine therapy to the patient, using clinical endpoints rather than

time to determine treatment duration. In the text, we describe a treatment approach for three common clinical scenarios based upon the type of ingestion and the clinical status of the patient. (See 'Duration of treatment' above.)

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•

We routinely measure the ALT prior to stopping acetylcysteine and continue

treatment if the ALT is abnormal, as some patients will develop liver injury during the treatment period. We also suggest remeasuring the serum acetaminophen concentration prior to stopping acetylcysteine to verify that the level is undetectable. (See 'Monitoring during treatment' above.) •

Between 10 and 20 percent of patients treated with IV acetylcysteine develop an

anaphylactoid reaction. Management depends upon the severity of the reaction and is described in the text. In the case of severe reactions (eg, respiratory difficulty), the infusion should be stopped and the clinician should obtain guidance from a medical toxicologist or poison control center. (See 'Anaphylactoid reaction' above and 'Additional resources' above.) •

Approximately 33 percent of subjects treated with oral acetylcysteine develop

nausea and vomiting. Serotonin 5-HT3 receptor antagonists (eg, ondansetron) are useful antiemetics. If the patient vomits within 60 minutes of an oral dose of acetylcysteine, the dose should be repeated. (See 'Vomiting' above.)

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GRAPHICS Severity of acetaminophen intoxication

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Relationship between plasma acetaminophen concentration (in µg/mL or µmol/L), the time after drug ingestion, and the risk of hepatic toxicity. The thick diagonal line of possible hepatic toxicity represents a 25 percent likelihood of disease. A relatively low level (such as 10 µg/mL) is safe soon after ingestion, but associated with appreciable risk at 24 hours since it reflects a high initial load which has now distributed into the tissues. Adapted from Rumack, BH,

Matthews, H, Pediatrics 1975; 55:873.

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