Para-Aminophenol Derivative

Decontamination with activated charcoal is recommended in cooperative adults within 2 hours of ingestion of (solid) immediate-release forms or within 4 hours of ingestion if greater than 30 g of acetaminophen (paracetamol) is ingested.[2][1]

 

In cases of massive acetaminophen (paracetamol) ingestion (greater than 50 g or serum concentrations greater than twice the nomogram line) doubling the final (16 hour) acetylcysteine infusion is recommended.[1] Hemodialysis may be beneficial in severe poisoning with very high blood concentrations, particularly if acetylcysteine is unavailable.[4]

 

Supportive care includes the continued use of acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence.

 

Advice should be sought from a specialist liver transplant unit:[1]

If 

Or

Or

Or

Or

Or

Or

 

Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy.

 

Emergency Stabilization

Decontamination

Antidote(s)

Enhanced Elimination

Supportive Care

Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. However, massive overdose may lead to early decline in level of consciousness and/or lactic acidosis.[5] Immediate attention should be given to the airways, assessment of blood glucose, and supportive care.[1] Definitive treatment is provided by the antidote acetylcysteine, with hemodialysis possibly indicated.[4] Carefully consider coingestant(s) or non-toxicological causes.

 

Gastrointestinal decontamination is not indicated in any pediatric (< 6 years old) patient following acetaminophen (paracetamol) overdose.[1]

 

Gastrointestinal decontamination with activated charcoal is only indicated:[1]

Further decontamination with activated charcoal may be necessary for co-ingestants.

 

Induction of emesis and gastric lavage are both contra-indicated.

 

Acetylcysteine is the treatment of choice for acetaminophen (paracetamol) overdose, and its intravenous use considered preferable.[7] When administered within eight hours of acetaminophen (paracetamol) ingestion it is almost completely effective in preventing death.[8] Use beyond this time is also beneficial and recommended.[3]

 

Intra-venous acetylcysteine infusion is indicated as outlined in the following links:

 

 

 

While acetylcysteine is recommended to be administered intravenously in 5% dextrose in water, 1/2 normal (0.45%) saline or normal saline (0.9%) may be substituted if necessary.[9] In children there is a risk of hyponatremia with 5% dextrose alone[10] and therefore normal (0.9%) saline should be used.

 

It is recommended that acetylcysteine dose for adults be calculated for actual body weight rounded up to the nearest 10 kg with a ceiling weight of 110 kg.[1]

 

CHILD

 

 

 

Children > 40 kg body weight:

 

 

 

 

Link to acetylcysteine dosing table for adults.

 

In the case of massive overdose (those whose acetaminophen (paracetamol) concentration is more than double the nomogram line) it is recommended that the final infusion over 16 hours is doubled to 200 mg/kg.[1]

 

 

ALT = alanine aminotransferase; BSL = blood sugar level; UEC = BUN (urea), electrolytes, and creatinine; LFTs = liver function tests; VBG = venous blood gases including pH and lactate.

 

* NOTE: If symptoms of hepatotoxicity (e.g. nausea, vomiting, abdominal pain or tenderness) then repeat ALT. Or if initial concentration more than double the nomogram line, then repeat ALT and paracetamol concentration at the completion of acetylcysteine.

 

Patients who have ALT > 50 U/L following completion of initial acetylcysteine require acetylcysteine to be continued at the rate of the last infusion stage (100 mg/kg acetylcysteine over 16 hours or 150 mg/kg/24 hours).[1]

 

Continue acetylcysteine until the patient is clinically improving, ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 66 umol/L (10 mg/L).[1][13]

 

Following chronic ingestion of acetaminophen (paracetamol) and commencement of acetylcysteine infusion, measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement.

Acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of acetylcysteine is not thought to be clinically significant,[14] however, delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.[15] Acetylcysteine is not considered teratogenic.[16]

 

Six to 23% of patients receiving IV acetylcysteine develop an anaphylactoid reaction.[17][18] These do not represent an immunological (allergic) reaction; rather, they are thought due to a direct dose-dependent effect on histamine release and generally occur within the first two hours of an infusion.

 

History of previous anaphylactoid reaction to acetylcysteine does not contraindicate use. If there is concern of recurrence of the reaction the patient may be pre-treated 15 minutes before commencement of the infusion with an antihistamine.[19]

 

Effects range from mild flushing to urticaria, angioedema, or bronchospasm. Hypotension may occasionally occur. Asthmatics appear more at risk. However, effects are usually easily managed and there is no reason to withhold acetylcysteine from any patient when indicated.[19]

 

 

Hyponatremia has been reported in children if administered acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.[10]

 

Increased International Normalized Ratio (INR) in the absence of acetaminophen-induced hepatic injury is relatively common.[20][21][22] It is important that increased INR alone (below 2) is not misinterpreted as evidence of acetaminophen-induced hepatic injury, as this may lead to unnecessarily prolonged acetylcysteine administration.[21]

 

In the majority of cases acetylcysteine is the only specific treatment required as acetaminophen (paracetamol) has a high endogenous clearance. However, acetaminophen (paracetamol) is moderately dialyzable,[23][24][25] and extracorporeal techniques may be beneficial in excessively large overdoses if acetylcysteine cannot be administered or where there is mitochondrial paralysis or other signs of severe poisoning.

 

Intermittent hemodialysis is recommended in any of the following situations:[4]

 

Intermittent hemodialysis is preferred but hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is not available. Exchange transfusion is an adequate alternative to hemodialysis in neonates.[4]

 

As acetylcysteine is dialyzable, acetylcysteine administration should be increased during hemodialysis. Up to 25% of acetylcysteine is removed by continuous renal replacement therapy and up to 50% with intermittent hemodialysis. The increase should match the expected losses from the extracorporeal technique.[4] It is recommended the dose is doubled while undergoing hemodialysis.[26][27]Hemodialysis should continue until clinical improvement is apparent.[4]

 

The following is initially recommended, however, further monitoring will be required should toxic effects become apparent.

 

Liver function tests:

Serum electrolytes:

Urinalysis

Renal function

Blood glucose

Full blood count

Blood gas analysis

Mental function

 

 

Hepatic monitoring should include:

 

 

Acetaminophen (paracetamol) can be nephrotoxic, even in the absence of hepatotoxicity (though this is uncommon).[29] Onset ranges from 2 to 5 days after overdose, with peak serum creatinine measured at 3 to 16 days.[28][30] The cause is acute tubular necrosis and may be more common in those with risk factors to acetaminophen (paracetamol) toxicity.[31] While the insult is typically reversible, interim support with hemodialysis may be required. Urea production will be reduced in the presence of hepatic failure and is therefore not a good index of renal function.[28] Advice should be sought from a liver transplant unit if creatinine is greater or equal to 200 umol/L (2.2 mg/dL).[32]

 

Patients should be monitored for the onset of renal failure:

 

Manage following standard treatment protocols for acute renal failure.

 

Coagulopathy is a common occurrence following acute hepatic failure. Coagulopathy should be managed in conjunction with hepatic failure. Alteration of coagulopathy is often seen before peak hepatic dysfunction.[33]

 

Patients should be monitored for increased International Normalized Ratio (INR).

 

 

Common in those with acetaminophen (paracetamol) induced acute hepatic failure and likely related to disseminated intravascular coagulation,[34] but rarely of significance in those without hepatotoxicity.[35] Monitoring for thrombocytopenia should be undertaken if acute hepatic failure develops. Platelets may be administered if the count is less than 50 x 10 to the power of 9/L.

Manage thrombocytopenia following standard treatment protocols.

 

Patients with glucose-6-phosphate dehydrogenase deficiency may be at risk of hemolysis following acetaminophen (paracetamol) overdose.[36][37][38]

 

Patients should be monitored for evidence of hemolysis:

Manage hemolysis following standard treatment protocols.

 

Hypotension may follow acetaminophen (paracetamol) ingestion[39] and is usually related to hepatotoxicity.

 

Patients should be closely monitored for onset of hypotension. Should this occur in association with hepatic failure, invasive hemodynamic monitoring is recommended as part of management.

 

In those with severe acetaminophen (paracetamol) poisoning, an electrocardiogram (ECG) during the first 48 hours may show minor non-specific S-T changes and T-wave flattening with U-waves, possibly related to hypophosphatemia. Serious cardiovascular abnormalities and hypotension, if they occur, are likely secondary to acute hepatic failure.[28]

 

Patients suffering acute hepatic failure from acetaminophen (paracetamol) toxicity should be monitored with an ECG for cardiac dysrhythmia.

 

Metabolic (lactic) acidosis following acetaminophen (paracetamol) overdose is typically a consequence of hepatic failure and should be treated as such. However, it has been described following massive overdose (associated with central nervous system depression) in the absence of clinical liver failure.[40][41] In such cases acidosis is considered due to early mitochondrial inhibition following glutathione depletion and before cellular damage.[42] Patients should be monitored for onset of acidosis if presenting with either very high acetaminophen (paracetamol) concentrations or depressed level of consciousness. Hemodialysis is recommended in patients presenting with an altered mental status, metabolic acidosis, and an elevated lactate with very high blood acetaminophen (paracetamol) concentrations, especially if NAC cannot be administered.[4] If hepatic injury is present, advice should be sought from a liver transplant unit if there is persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L.[1]

 

Monitor:

Manage metabolic acidosis following standard treatment protocols.

 

Hypoglycemia has been reported[43] and is most likely a consequence of acute hepatic failure and should be managed in conjunction with this condition. Patients with severe hepatic failure should be monitored for hypoglycemia.

 

Monitor serum glucose.

 

 

Hypophosphatemia may occur as a result of either hepatic or renal failure due to acetaminophen (paracetamol) overdose,[44] but would appear more likely due to the later.[45]

Monitor serum phosphate

Manage hypophosphatemia following standard treatment protocols.

 

Acute lung injury has been reported as common in those suffering acetaminophen (paracetamol) induced fulminant hepatic failure.[46]

Non-cardiogenic pulmonary edema may manifest with desaturation and pulmonary rales. On occasion frothy, pink sputum may be apparent. Investigations for this condition should include:

 

Manage non-cardiogenic pulmonary edema following standard treatment protocols.

 

Pancreatitis occurs rarely following acetaminophen (paracetamol) overdose, and appears related to prior alcohol intake or hemorrhage rather than direct acetaminophen (paracetamol) toxicity. Patients should be monitored for pancreatitis if dehydration is suspected, or their presentation is late.[35]

Observe for:

Monitor:

 

Manage pancreatitis following standard treatment protocols.

 

Patients suffering acetaminophen (paracetamol) overdose may be medically discharged following the initial (20 to 21 hour) acetylcysteine infusion provided:

 

 

In other cases continued acetylcysteine infusion (100 mg/kg per 16 hours) is required until improvement.[47] If continued infusion is required discharge may occur when liver function tests, International Normalized Ratio (INR), and creatinine are shown to be normalizing.

 

Discharge after development of hepatic or renal failure, or other consequences, should follow standard protocols for those conditions.

 

Standard protocols should be used for follow-up of patients suffering hepatic or renal failure, including advice that patients should abstain from alcohol for six weeks to allow regeneration of the liver.

 

Patients should be referred for psychiatric assessment as appropriate.

 

Full recovery from both hepatic and renal damage due to acetaminophen (paracetamol) toxicity is usual, but not inevitable.

Anorexia[49][43][56]

Nausea[49][43]

Vomiting[49][43]

Abdominal pain[57][58][59]

Hyperamylasemia[57][60][61][62] (uncommon)

Pancreatitis[57][60][61][62] (uncommon)

 

Elevated liver enzymes[43][63][64][65][66][67]

Increased International Normalized Ratio (INR)[65][68][69]

Coagulopathy[50][68]

Jaundice[43][59][62][70]

Hepatic encephalopathy[64][66][71][56]

Centrilobular hepatic necrosis[56]

 

Proteinuria[74]

Hematuria[74]

Acute tubular necrosis[43][65][75][76][56]

Renal failure[43][65][74][77][78]

 

 

 

Pallor[5][86][87]

Diaphoresis[49]

 

Coagulopathy[50][68]

Increased International Normalized Ratio (INR)[65][68][69][52]

 

Symptoms in chronic situations are broadly similar to acute ones. Heptotoxicity and its complications are the major concern.[88][87]

 

Children appear less susceptible to hepatotoxicity from acetaminophen (paracetamol) than adults. Toxicity following pediatric exploratory ingestions is rare.[1][89] However, the exact toxic dose is still subject to debate. Oro-dispersible formulas may present an increased risk over standard tablets due to their near immediate disintegration when in contact with saliva.[54]

 

Medical attention is warranted for ingestions of 200 mg/kg or more in children 6 years or under, or the lesser of 10 g or 200 mg/kg in children over 6 years.[1][90]

 

Acetaminophen (paracetamol) induced hepatotoxicity may occur in adults after large doses. In a study of patients over 12 years of age, a single dose of less than 12 g can cause severe hepatotoxicity, and death has occurred with doses over 15 g.[91]

 

Medical attention is warranted following ingestions of the lesser of 10 g or 200 mg/kg acetaminophen (paracetamol).[1][90]

 

Chronic overdose, for example ingestion of several high 'therapeutic' doses of acetaminophen (paracetamol) over 1 to 2 days, or multiple minor overdoses over a short period of time, may produce moderate or even severe hepatic damage.[88][92]

 

The staggered dose required to produce acetaminophen (paracetamol) toxicity has yet to be established.

 

Medical attention is warranted for children 6 years or under who ingest 200 mg/kg or more over a single 24 hour period, 150 mg/kg per 24 hours for the preceding 48 hours, or 100 mg/kg per 24 hours more than 48 hours.[1]

 

Medical attention is warranted for adults and children over 6 years who ingest the lesser of 10 g or 200 mg/kg or more over a single 24 hour period, the lesser of 6 g or 150 mg/kg per 24 hours for the preceding 48 hours, or the lesser of 4 g or 100 mg/kg per 24 hours for more than 48 hours in patients with symptoms indicating possible liver injury e.g. abdominal pain or nausea or vomiting.[1]

 

 

Cats are very susceptible to toxicity as they have limited ability to metabolize acetaminophen (paracetamol) due to a limited capacity of their glucuronidation pathway and/or saturation of their sulfate conjugation pathway.[95] As little as 50 to 60 mg/kg orally may be toxic.[96]

 

Signs may occur within a few hours of ingestion and include depression, anorexia, vomiting, cyanosis, edema of the face and extremities, methemoglobinemia, dyspnea, hepatotoxicity, and death. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%.[96] Cats typically do not develop major hepatotoxicity although this may be due to cats dying from hypoxia secondary to methemoglobinemia at doses that are too low to produce hepatic necrosis.[96]

 

Cat

 

 

Dogs do have the ability to metabolize acetaminophen (paracetamol), however, methemoglobinemia is a concern as is hepatic damage. Toxic doses for dogs are probably greater than or equal to 150 mg/kg.[96]

 

Signs develop within one to two hours of ingestion and are progressive, consisting of anorexia, salivation, vomiting, hypovolemia, depression, methemoglobinemia, hematuria or hemoglobinuria, and edema of the face and/or paws. Muscle tremors or rarely seizures may occur, possibly through triggering of latent epilepsy. Hematuria and hemoglobinuria usually appear first, when blood methemoglobin levels are around 20%. Signs may persist 12 to 48 hours. Acute hepatic failure may follow initial signs. Death may occur 18 to 36 hours post ingestion.[96]

 

Dogs administered 3 doses of 750 mg/kg initially, 200 mg/kg 9 hours later, and 200 mg/kg at 24 hours after the initial dose by subcutaneous injection consistently developed fulminant hepatic failure. No deaths occurred within the first 36 hours.[98]

 

Dog

 

A serum concentration versus time curve or Acetaminophen (Paracetamol) Nomogram has been constructed to provide an indication of potentially hepatotoxic acetaminophen (paracetamol) serum concentrations. Note this graph displays the acetaminophen (paracetamol) concentration in both umol/L and mg/L.

 

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.

 

Generally, indicated for:[114][115][116]

 

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.

 

Oral

Rectal

Injection

 

The pharmacological action of acetaminophen (paracetamol) is not fully understood. It has been hypothesized that the mechanisms involved for producing analgesia and antipyrexia are similar to that of the salicylates but with only weak anti-inflammatory effects.

 

It is known that acetaminophen (paracetamol) selectively inhibits prostaglandin synthesis, predominantly in the central nervous system and to a lesser extent in the periphery.[121] Acetaminophen (paracetamol) also lowers body temperature by acting on the hypothalamus to increase vasodilatation and peripheral blood flow to aid heat dissipation. This occurs largely in patients with a fever, with little change in body temperature in subjects with normal body temperature. Acetaminophen (paracetamol) is also a weak inhibitor of the enzyme cyclo-oxygenase, but only in the presence of a high concentration of peroxides.[122]