by Okoh  F. Richard

 

OUTLINE

  • INTRODUCTION
  • EPIDEMIOLOGY
  • MECHANISM OF ACTION
  • METABOLISM
  • ACETAMINOPHEN TOXICITY
  • PATHOPHYSIOLOGY
  • MANAGEMENT
  • DIFFERENTIAL DIAGNOSIS
  • COMPLICATION
  • CONCLUSION
  • REFERENCES

 

INTRODUCTION

Acetaminophen is the most commonly used analgesic-antipyretic over-the-counter medication.

Its use has largely replaced salicylates due to the reduced risk of gastric ulceration.

It is a major ingredient in numerous cold and flu remedies.

Due to its wide availability, it can be unintentionally ingested by children, taken in an intentional overdose by adolescents and adults or inappropriately dosed in all ages.

It is one of the most common drug poisoning in the world and can produce severe hepatotoxicity.

In children, toxicity most commonly results from repeated overdosage arising from confusion about the age-appropriate dose and use of multiple products that contain acetaminophen or use of adult suppositories.

 

EPIDEMIOLOGY

It is the second most common reason for liver transplant worldwide.

It is more common in children; however adults often present with a more serious and fatal presentation.

The American Association of Poison Control Centers’ National Poison Data System reported 53,295 single exposures to acetaminophen alone in 2019, and 28,789 single exposures to acetaminophen in combination with other drugs.

In Nigeria however, there is paucity of data following acetaminophen poisoning.

 

MECHANISM OF ACTION

Acetaminophen  is also known as N-acetyl-p-aminophenol.

It inhibits cyclooxygenase enzymes in central nervous system.

It blocks the formation and release of prostaglandins, inhibiting the direct action of endogenous pyogens

 

METABOLISM

Acetaminophen is completely and rapidly absorbed from the gastrointestinal tract and reaches therapeutic levels in 30 min to 2 hours.

Peak plasma level is within 4 hours

Metabolism primarily occurs through glucuronidation (60%) and sulfation (30%)  which occur in the liver.

5-8% is metabolized by CYT P450 pathway; 2% is excreted unchanged in urine.

Acetaminophen is oxidized to form intermediate NAPQI ( N– acetyl- p– benzoquinone imine) this in turn conjugate with hepatic glutathione and are excreted in the urine.

 

ACETAMINOPHEN TOXICITY

It produces dose-dependent hepatotoxicity

Recommended dose of paracetamol for adults is 650mg to 1000mg every 4 to 6 hours, not to exceed 4g/day.

In children the dose is 15mg/kg up to 60mg/kg/day.

To cause toxicity, an acute oral overdose must total > 150mg/kg (7.5g in adults) within 24hrs.

 

Pathophysiology

Overdose levels peak at 4 hours, these pathways are saturated and more acetaminophen is subsequently metabolized to NAPQI

Glutathione stores in the liver detoxify this metabolite.

An acute overdose depletes glutathione stores in the liver

NAPQI accumulates causing hepatocellular necrosis and possibly damage to other organs.

 

CLINICAL STAGE OF ACETAMINOPHEN POISONING

Stage Time Postingestion Description
I 0–24 hours Anorexia, nausea, vomiting, malaise, pallor
II 24–72 hours Right upper quadrant abdominal pain (common)

AST, ALT, and if poisoning is severe, bilirubin and PT (usually reported as the INR) sometimes elevated
III 72–96 hours Vomiting and symptoms of liver failure

Peaking of AST, ALT, bilirubin, and INR

Sometimes renal failure.
IV > 5 days Resolution of hepatotoxicity or progression to multiple organ failure (sometimes fatal)

 

GENERAL MANAGEMENT

Acetaminophen poisoning is an emergency because the longer the poison stays, the more the distribution and the worse the outcome.

Assess properly in the emergency room; strict attention to the  ABC’s of resuscitation.

Simultaneous History taking

  • All possible products ingested
  • Time of ingestion,
  • Amount ingested,
  • Current symptoms

Simultaneous Examination

  • Vitals, systemic examination

 

INVESTIGATIONS

Complete blood count

Electrolytes /urea/ creatinine

Plasma Acetaminophen level

Liver function test

Arterial Blood Gas

Prothrombin time with international normalized ratio (INR)

Urinalysis

Blood and urine toxicology screening

HCV, HBsAg

Blood glucose

 

Specific Management

If < 4 hours (less than 4hours):

  • Treatment of choice is activated charcoal
  • It is charcoal that has been treated with oxygen and activated by exposure to high heat.
  • Give a dose of 1g/kg (max 50g).
  • Ipecac, lavage not recommended.

If >/= 4 hours (equals to or more than 4hours) and suspicious of large overdose > 7.5g:

  • Start antidote
  • N- Acetylcysteine (NAC) is a precursor of glutathione. Available in oral and Intravenous form.
  • N-Acetylcysteine given by IV 150mg/kg over 1hr; then 50mg/kg over 4 hours followed by 100mg/kg over 16hours
  • N-Acetylcysteine given orally 140mg/kg loading dose, followed by 70mg/kg every 4hrs for 17 doses
  • Stop if level below therapeutic line and INR/LFT normal
  • Alternative is methionine.

If time of overdose is unknown:

    • Start NAC(N-acetylcysteine)
    • Determine serum acetaminophen levels
    • Determine INR(International Normalized Ratio) levels and LFT
    • Continue treatment with N-acetylcysteine if serum acetaminophen levels detected or transaminases are detected. 
    • Any patient with serum acetaminophen poisoning in the possible or probable hepatotoxicity range should be treated with NAC.

      If time of ingestion is unknown, acetaminophen level >20microgram/ml, even with normal LFT patient should be treated with NAC

      Any patient with history of chronic supratherapeutic ingestion or low glutathione stores but no toxic ingestion should be treated with NAC

      Patients with signs of hepatotoxicity, even with a low or nondetectable acetaminophen level are also candidates of antidotal therapy

 

DIFFERENTIAL DIAGNOSIS

Viral hepatitis

Gastroenteritis

Amatoxin toxicity

Wilson’s disease

 

COMPLICATION

  • Acute liver failure
  • Steven-Johnson syndrome / Toxic epidermal necrolysis
  • Acute generalized exanthematous pustulosis

Acute liver failure

Acute liver failure (ALF) is a condition in which rapid deterioration of the liver function results in coagulopathy and alteration in the mental status of a previously healthy individual

Evidence of coagulation abnormality , usually an INR ≥ 1.5, and any degree of mental alteration (encephalopathy) in a patient without pre- existing cirrhosis & with an illness of < 26 weeks duration.

Signs and symptoms of acute liver failure may include the following:

  • Encephalopathy
  • Cerebral edema: May lead to signs of increased intracranial pressure (ICP) (eg, papilledema, hypertension, bradycardia)
  • Jaundice- Often present but not always
  • Ascites- Potential for hepatic vein thrombosis with rapid development in the presence of fulminant hepatic failure accompanied by abdominal pain
  • Right upper quadrant tenderness: Variably present
  • Change in liver span: May be small due to hepatic necrosis or may be enlarged due to heart failure, viral hepatitis, or Budd-Chiari syndrome
  • Hematemesis or melena: Due to upper gastrointestinal (GI) bleeding
MANAGEMENT OF ACUTE LIVER FAILURE

Multidisciplinary:-

Managing fulminant hepatic failure is a team effort. Consultations with specialists in intensive care, gastroenterology, infectious diseases, hematology, neurology, neurosurgery, and transplantation surgery may be needed to address the myriad complex issues that can confront the medical staff.

Management of Encephalopathy

Patients with grade I encephalopathy may sometimes be safely managed in a medicine ward.

Unmanageable agitation may be treated with short-acting benzodiazepines in low doses.

Identify and remove possible precipitants ( drugs, sepsis, gastrointestinal bleeding,  constipation,  infection, electrolyte derangements, aggressive paracentesis,  indiscriminate  diuretic use, high protein diet).

Management of Cerebral edema

The occurrence of cerebral edema and intracranial hypertension (ICH) in patients with acute liver failure is related to the severity of encephalopathy.

Cerebral edema is seldom observed in patients with grades I-II encephalopathy. The risk of edema increases to 25-35% with progression to grade III and increases to 65-75% (or more) in patients reaching grade IV coma.

Hence such patients should be managed in the ICU via :-

1.20% mannitol IV

2.Hyperventilation

Administration of IV mannitol (in a bolus dose of 0.5-1 g/kg or 50-100 g) is recommended to treat ICP in acute liver failure.

If life-threatening ICP is not controlled with mannitol infusion, hyperventilation may be instituted temporarily in an attempt to acutely lower the ICP and to prevent impending herniation.

Management of Coagulopathy

Give fresh frozen plasma

One unit of FFP(Fresh Frozen Plasma) increases the coagulation factor by 5%; 2 units increase it by 10%.  A FFP infusion of 15 mL/kg of body weight or 4 units will correct the deficiency.

If the fibrinogen level is very low (< 80 mg/dL), consider administering cryoprecipitate.

Whole blood can also be used.

 

Liver Transplantation

Liver transplantation is the definitive treatment in liver failure

It remains the only effective therapy for ALF patients who fail to recover spontaneously.

King’s College criteria is used to select the patient that should be referred to a transplant center for transplantation.

 

King’s college criteria

Used to determine which patient should be referred for consideration of liver transplant. It includes:

1.Acidosis ( pH <7.3)

2.Coagulopathy (prothrombin time >100sec)

3.Renal dysfunction (creatinine level > 3.4mg/dl)

4.Hepatic encephalopathy (grade III or IV)

 

Suicidal attempt

Following acetaminophen poisoning with intentional overdose, patient should be referred to a psychiatrist for further evaluation, counselling and management.

 

Prognosis

With appropriate treatment, mortality is uncommon.

Poor prognostic indicators at 24 to 48 hours post ingestion include all of the following:

  • pH < 7.3 after adequate resuscitation
  • Serum creatinine > 2.6
  • Hepatic encephalopathy grade III (confusion and somnolence) or grade IV (stupor and coma)
  • Hypoglycemia
  • Thrombocytopenia

Acute acetaminophen toxicity does not predispose patients to cirrhosis.

If a patient is diagnosed and treated promptly, the mortality of acetaminophen toxicity is less than 2%

Of the patients who progress past clinical stage 3, 99% have clinical resolution

About 1-3% of patients with liver failure need to undergo liver transplant as a life saving measure

Patients adequately managed are expected to fully recover and have a normal life expectancy and quality of life

 

Recommendation

It is crucial to increase awareness and understanding of the general population with regards to acetaminophen dosing and toxicity.

Limiting the amount of over-the-counter (OTC) analgesics in a single container and eliminating confusing and redundant formulations

Doctors and Pharmacist play an important role in educating about the toxicity of acetaminophen.

Patient should not take over 4 grams of acetaminophen/day.

Threshold may be lower for patients with liver disease or cirrhosis.

Acetaminophen should be kept out of reach of children.

 

Conclusion

Acetaminophen is contained in >100 products sold over the counter and consequently, its overdose is common.

NAC is 100% effective in preventing hepatotoxicity if started within 8 hours of ingestion.

In overdose, it causes significant morbidity and mortality.

The burden to health care services is considerable, therefore the importance of educating the family about the potential toxicity of acetaminophen cannot be overstated.

 

REFERENCE

[Guideline] US Food and Drug Administration. Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use–Labeling for Products That Contain Acetaminophen. Federal Register– Docket Number FDA-2012-D-0529. Available at https://www.fda.gov/media/83588/download. November 2015; Accessed: October 2, 2022.

Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. BMJ. 2011 Apr 19. 342:d2218. [QxMD MEDLINE Link].

Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Brooks DE, Dibert KW, et al. 2019 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 37th Annual Report. Clin Toxicol (Phila). 2020 Dec. 58 (12):1360-1541. [QxMD MEDLINE Link]. [Full Text].

Strom, C. (2019, August 27). Difference Between Charcoal and Activated Charcoal. Difference Between Similar Terms and Objects. http://www.differencebetween.net/science/difference-between-charcoal-and-activated-charcoal/.

[Guideline] Lee WM, Larson AM, Stravitz RT. AASLD position paper: the management of acute liver failure: update 2011. Hepatology. Available at https://www.aasld.org/sites/default/files/guideline_documents/alfenhanced.pdf. 2011; Accessed: November 13, 2022.

Tsai CL, Chang WT, Weng TI, Fang CC, Walson PD. A patient-tailored N-acetylcysteine protocol for acute acetaminophen intoxication. Clin Ther. 2005 Mar. 27(3):336-41. [QxMD MEDLINE Link].