The major manifestation of paracetamol poisoning is hepatotoxicity, although the kidneys and heart may also be affected in severe poisoning. N-acetylcysteine (NAC) prevents toxicity if given within the first eight hours. NAC is also of benefit in patients presenting late or with established hepatotoxicity. Decisions about treatment are based on the plasma concentration in patients who present early and the dose ingested and/or clinical signs in those presenting late.
There are numerous guidelines published for the treatment of paracetamol related toxicity. Often these are based on local or historical practices and therefore it is not unusual to find significant variation amongst the guidelines. The risk assessment and treatment guidelines outlined in this monograph are based on Australasian Guidelines for the Treatment of Paracetamol Toxicity (Daly et al. 2008).
Paracetamol (known as acetaminophen in the US and Canada) is found in multiple combined analgesic preparations and the strengths vary considerably. There are two modified release products now available with different kinetics in therapeutic use. In Australia a modified release preparation containing 665mg of paracetamol (31% immediate release, 69% sustained release) is marketed under three different trade names (Panadol Osteo, Panadol Extend and Duatrol SR).
Paracetamol can produce multiorgan failure via the production of an intermediate toxic metabolite. Minor oxidative pathways (P450 enzymes, mainly CYP2E1) produce the intermediate toxic metabolite N-acetyl-p-benzoquinonimine that requires glutathione for further metabolism to non-toxic metabolites. After glutathione supplies are exhausted, the toxic metabolite binds to sulphydryl (SH)- containing proteins in the liver cell and causes lipid peroxidation disrupting the cell membrane. These events eventually lead to cell death. Any organ that has P450 enzymes can suffer toxicity (i.e. liver, kidneys, heart, and pancreas).
There are a number of variables which potentially influence the risk of toxicity. These are best appreciated by understanding the toxicokinetics of paracetamol.
Detailed Graphic for The Metabolism of Acetaminophen and the Synthesis of Glutathione
Detailed enzyme pathways for paracetamol/acetaminophen toxicity [need link]
Theoretically, toxicity is more likely if the P450 enzymes are induced by chronic alcohol ingestion, anticonvulsants, or barbiturates.
Inhibition of P450 enzymes (e.g. by acute alcohol ingestion (4-6 drinks), or medicines) at the time of the overdose reduces the production of toxic metabolites.
Patients who are depleted of glutathione (e.g. malnutrition, eating disorders) are also theoretically at increased risk of toxicity.
Increased sulphation enzyme activity (seen with oral contraceptives and in children) will increase elimination by non-toxic conjugation.
Paracetamol is normally rapidly absorbed and peak concentrations occur within 1-2 hours for standard tablet or capsules and even quicker (< 0.5 h) in liquid preparations. There are two sustained release preparations and absorption from these continues for up to 12 hours in therapeutic doses and much longer in overdose. (This means the nomogram cannot be used with SR preparations).
Prolonged absorption is seen following large ingestions (> 500 mg/kg) and with coingestion of drugs that slow gastrointestinal motility ( opiates & anticholinergic)
After absorption, paracetamol distributes rapidly with a volume of distribution of 0.9 L/kg.Absorption and distribution are completed by 4 hours post overdose with standard release preparations and within 2 hours in liquid preparations.
Paracetamol is metabolised by a number of pathways. The majority of metabolism is by glucuronidation and sulphation. There is some first pass metabolism (about 20%) due to sulfation in the gut wall. The half-life of paracetamol in therapeutic use is 1.5 to 3 hours. The half-life may become prolonged in overdose to greater than 4 hours. A prolonged half-life has been linked to a higher risk of toxicity, which may indicate this is due to saturation of conjugation pathways and an increasing proportion of paracetamol being metabolised by P450 enzymes.
The minor pathways involving P450 enzymes account only for about 5-10% of paracetamol metabolism in therapeutic use. These lead to production of a toxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). This conjugates with glutathione and is excreted as a non-toxic conjugate in the urine. As glutathione is depleted, this reactive metabolite binds covalently to hepatic macromolecules leading to cell dysfunction and death.
Hepatotoxicity is the major clinical effect. A rise in the transaminases (ALT, AST) occurs within 24 hours and will usually peak 3-4 days later. Very high AST and/or ALT is seen with significant toxicity, (» 1,000 U/L). The extent and speed of ALT rise has been linked with subsequent severity. (Sivilotti 2010)
Patients may complain of anorexia, nausea, vomiting, and hepatic tenderness.
They may develop any of the following complications:
See also prognostic indicators in hepatotoxicity.
Acute renal failure with acute tubular necrosis is usually reversible. It occurs in only a small proportion of patients with hepatotoxicity, but does indicate a worse prognosis. A history of chronic alcohol use is generally given and on rare occasions, it may occur in individuals with little hepatotoxicity.
All adults should have a PLASMA PARACETAMOL CONCENTRATION at 4 hours post overdose, or as soon as possible if presentation is after 4 hours, irrespective of reported ingested dose. Children 1-5 years of age with accidental ingestion do not need a paracetamol concentration drawn unless the possible ingested dose is > 225 mg/kg (> 200 mg/kg Australasian guidelines). In that case, draw the concentration at 2 hours (for elixir preparations) or 4 hours (for tablet preparations) and plot on the nomogram.
The following investigations should be done in all patients at significant risk of hepatotoxicity [generally those with high paracetamol concentrations and NAC treatment later than 6-8 hours (Sivilotti 2005)]:
Conversion factor for paracetamol concentrations
Plasma paracetamol should be estimated urgently in any patient who presents unconscious with a drug overdose. The purpose of this is to look for evidence of paracetamol exposure and determine the potential severity of the poisoning using the nomogram.
Paracetamol levels should be repeated prior to ceasing treatment with NAC in patients with controlled release preparations or patients with very large ingestions.
Coagulation studies should be done at least daily in patients who have a substantial transaminase rise. These are the best prognostic indicators for paracetamol-induced liver failure. A very poor prognosis is indicated by:
For more detail see hepatotoxicity below.
Due to the importance of the prothrombin time as a prognostic indicator, fresh frozen plasma should not be given unless there is active bleeding. Vitamin K may be given, however it will only correct the INR if there is coexistent vitamin K deficiency or coumarin anticoagulant ingestion.
The INR may be elevated (typically to around 1.5, but sometimes up to 2.5) in up to 50% of paracetamol poisoned patients without any evidence of hepatotoxicity. This rise in INR is time, dose, and concentration dependent and is due to inhibition of the activation of coagulation factors. It occurs earlier than the rise associated with hepatotoxicity and should not be confused with the prognostic rises discussed above (Whyte et al, 2000).
Patients with hepatotoxicity will require daily measurement of electrolytes and creatinine. This is to detect renal failure, acidosis and electrolyte abnormalities due to hepatic failure.
Patients who develop hepatotoxicity require regular measurement of their blood glucose, particularly in those patients who are unable to eat. Patients may become hypo- or hyperglycaemic. However, hyperglycaemia should not be corrected unless it is very high.
An early rise (at 24 hours) in transaminases (ALT, AST) is an indicator of potentially serious hepatotoxicity. Almost all patients who will go on to develop hepatotoxicity (ALT or AST > 1,000 IU) will have abnormal transaminases at 24 hours. Peak enzymes in patients who recover usually occur between 2 and 4 days post overdose. The prothrombin time is the best single prognostic indicator.
In the initial assessment of the potential risk of the poisoning there are 3 areas that may be considered. The usefulness of each is dependent on the nature of the presentation:
The ingested dose is useful in risk assessment in the following clinical scenarios:
A conservative estimate of a dose with the potential for hepatotoxicity if untreated in an adult is greater than 150 mg/kg body weight. The safety margin at this dose is considerable and the minimum risk dose may be closer to 200 mg/kg. Australasian guidelines suggest an allowable dose of up to 200 mg/kg over a 24 hour period, or 150 mg/kg per 24 hour period over the preceding 48 hours (see treatment section).
Recent data supports a minimum risk dose for children 1-5 years of age of 225 mg/kg (200 mg/kg Australasian guidelines). A dose less than 150 mg/kg in an adult is very unlikely to produce hepatotoxicity, although the reported dose ingested is often inaccurate. In addition, many other factors such as vomiting, first pass metabolism, coingested drugs, and age may influence the paracetamol concentration achieved after a given dose.
A conservative approach to give some safety margin for inaccuracies in dose estimation, would entail treatment of any adult who had taken more than 150 mg/kg in a 24 hour period with the exception of patients who define themselves as low risk by paracetamol concentration.
Paracetamol concentrations taken between 4 and 12-15 hours after an acute single ingestion correlate with clinical severity when plotted on the Rumack/Matthew nomogram.
A simplified derivative of the Rumack/Matthew nomogram is recommended for risk assessment following paracetamol overdose in Australia and New Zealand. The aim of the nomogram is to rationalise the evidence regarding risk factors (see section “high risk patients”) while using a single treatment line to simplify decision making.
Paracetamol Treatment Nomogram for Australia and New Zealand (Daly et al. MJA 2008)
The line between 15 and 24 hours has been extrapolated. This part of the line is close to the level of quantification and therefore low paracetamol concentrations are more difficult to interpret. Any detectable paracetamol concentration measured between 15 and 24 hours post exposure should be interpreted conservatively and in general treatment with N-acetylcysteine is indicated until it is clear if hepatotoxicity is developing. As ALT generally rises within 24 hours, NAC can be stopped in the asymptomatic patient if 24 hours have elapsed if the ALT is normal and paracetamol is less than 100 umol/L (15mg/L.
Patients with uncertain time of ingestion can be treated:
The following are examples of latter two techniques.
Worst case analysis
For example, a paracetamol concentration of 910 micromol/L is likely to require treatment if more than 4 hours might have elapsed.
Determination of paracetamol half-life
A half-life greater than 4 hours indicates a high risk of hepatotoxicity.
Take 2 concentrations about 2 hours apart (e.g. first concentration: 700 micromol/L, concentration 2 hours later: 580 micromol/L)
You can then either:
1. Plot them anywhere on the nomogram (see example). If the slope of the line joining these concentrations is flatter than the treatment line then the half-life is > 4 hours and the patient requires treatment.
2. Calculate half-life using this formula:
Half life = ln 2 * [T2-T1] / [ln C (T1) - ln C (T2)]
[T2-T1] is the time between samples. ln C (T1) & ln C (T2) are the natural logs of the concentrations)
e.g. Half life =ln2 * 2 hours/ (ln 700 - ln 580)
0.693 * 2/ (6.551 - 6.363) hours = 7.35 hours
3. If the samples are exactly 2 hours apart and the half-life is greater than 4 hours, then the second sample will be greater than 70% of the first sample
e.g. 580 is greater than 490 (70% of 700) therefore half life is greater than 4 hours
Patients who have a delayed presentation (>15 hours) or who have already developed hepatitis need to be assessed using different criteria as the nomogram has not been validated for this group of patients. Initial treatment should be based on dose ingested and the presence of symptoms or signs of hepatotoxicity. Liver function tests and a paracetamol concentration should be measured.
If at 24 hours after the overdose, the patient is asymptomatic, liver function tests are normal and plasma paracetamol concentration is undetectable, they will not develop significant toxicity. The presence of abnormal transaminases or a measurable concentration of paracetamol indicates there is still a potential risk of significant hepatotoxicity.
Almost all patients who develop hepatotoxicity will have abnormal transaminases (ALT or AST > 2 x ULN) by 24 hours.
Peak hepatotoxicity in patients who recover usually occurs between 2-4 days post overdose. The prothrombin time is the best prognostic indicator in those with established hepatotoxicity.
In children 1-5 years of age exposed to paracetamol elixir, concentrations should only be measured if the ingested dose is > 225 mg/Kg. Blood can be taken as early 2 hours after exposure in this circumstance.
Management flow chart for acute paracetamol exposure with known time of ingestion (Daly et al. MJA 2008)
Oral activated charcoal should be given to all adults and older children ingesting more than 200 mg/kg or 10g (whichever is less) of paracetamol standard release tablet or capsule preparations presenting within 1 hour. For children 1-5 years of age, the at risk dose is > 200 mg/kg. If an elixir preparation is taken, absorption is so rapid GI decontamination is not indicated.
N-acetylcysteine is a glutathione precursor and is a source of sulphydryl groups that allows the intermediate toxic metabolite to be conjugated to non-toxic metabolites. It also may have secondary benefits as an antioxidant (preventing lipid peroxidation) and as a free radical scavenger.
Treatment offers near complete protection from toxicity if started within 8 hours of ingestion.
Treatment greater than 8 hours lowers mortality but offers incomplete protection from hepatotoxicity.
Dosage protocol for intravenous N-acetylcysteine (Parvolex)
The treatment may be continued for longer than 20 hours in late presentations and patients with evidence of liver damage by continuing the infusion rate at 50 mg/kg in 500 mL of 5% Dextrose over 8 hours (see late presentations).
p>Alternate protocols are being actively investigated with evidence of reduced adverse effects and probable comparable efficacy. see SNAP trial
Children > 20 kg
The treatment may be continued for longer than 20 hours in late presentations and patients with evidence of liver damage by continuing the infusion rate at 50 mg/kg in 250 mL of 5% Dextrose over 8 hours (see late presentations).
Children < 20 kg
The treatment may be continued for longer than 20 hours in late presentations and patients with evidence of liver damage by continuing the infusion rate at 50 mg/kg in 7 mL/kg of 5% Dextrose over 8 hours (see late presentations).
140 mg/kg as a 5 percent solution (diluted in soft drink, juice, or water) then
70 mg/kg per dose every four hours for 17 doses
The total dose over 72 hours is 1,330 mg/kg.
In late presentations of patients with evidence of liver damage convert to intravenous therapy at the infusion rate at 50 mg/kg in 500 mL of 5% Dextrose over 8 hours (see established hepatotoxicity).
Nausea, vomiting and diarrhea are common after oral and IV therapy.
Anaphylactic reactions can occur with intravenous N-acetylcysteine in up to 20-25% of patients and rarely in oral therapy. They are due to drug induced histamine release, are dose related and not due to an allergic response. Asthmatics have an increased risk of reactions.
Anaphylactic reactions commonly occur with the initial loading dose in the first hour of treatment. The infusion should be ceased temporarily. An antihistamine should be given in severe cases although most reactions settle without specific treatment. Once the reaction has settled, recommence the infusion (if still indicated) at 25% of previous rate, increasing to the normal rate over the next hour.
Ondansetron should be avoided as there is preliminary evidence that it increases risk of hepatic injury.
The management is determined by the time from ingestion until a paracetamol concentration can be obtained but is modified in high-risk patients:
Less than 8 hours post overdose
If the patient has taken a POTENTIALLY TOXIC DOSE > 200 mg/kg body weight or 10g (whichever is less) and presents within one hour then activated charcoal should be given unless an elixir has been taken.
Blood is taken for a paracetamol concentration at 4 or more hours post ingestion. If the paracetamol concentration is above the treatment line on the nomogram, N-acetylcysteine is commenced.
If the result of the paracetamol concentration will not be available within 8 hours of ingestion and the dose is above the risk level, commence N-acetylcysteine while awaiting the result.
Patients 8 - 15 hours post overdose
N-acetylcysteine is given to any patient who has ingested a dose greater than 200 mg/kg body weight or 10g (whichever is less). A plasma paracetamol concentration is taken and treatment may be ceased if the concentration is below the treatment line on the nomogram.
Late presentation (after 15 hours)
Patients who have a delayed presentation (>15 hours) or who have already developed hepatitis require a longer than usual course of N-acetylcysteine treatment and close supportive care.
N-acetylcysteine is started if ingested dose is greater than 200 mg/kg body weight or 10g (whichever is less) or their liver function tests are abnormal. The infusion should be continued as below if hepatotoxicity develops. The infusion should be ceased if the patient is asymptomatic, liver function tests are normal and plasma paracetamol concentration is undetectable.
Patients with established hepatotoxicity
These patients should all be commenced on N-acetylcysteine. If they have already received N-acetylcysteine, this should be continued at an infusion rate of 50 mg/kg per 8 hours until their prothrombin time and liver enzymes (ALT and AST) begin to plateau or fall.
High risk patients
Many guidelines advise that patients at high risk by virtue of being on enzyme inducing drugs, having chronic alcohol use or malnutrition should receive N-acetylcysteine at a lower threshold for treatment than other patients. This is a controversial issue and there is a lack of consensus amongst clinical toxicologists. Many treatment nomograms use a high risk treatment line that runs parallel to, but at lower (50% less) corresponding concentrations to the traditional non-high-risk line. Other recommendations when using these a nomogram with a high-risk line include commencing treatment in high-risk patients if more than 100 mg/kg has been ingested and concentrations are unavailable within 8 hours.
The Australasian treatment guidelines are based on a consensus amongst local clinical toxicologists and seek to rationalise the evidence regarding high-risk patients. The treatment nomogram has only one treatment threshold line and builds in a degree of safety for those patients that may possess risk factors for the development of paracetamol toxicity.
Treatment decisions based on the half-life of paracetamol as described earlier, should not be used in patients who have potential high-risk factors for the development of paracetamol toxicity.
Staggered or multiple ingestions
Patients who present with a history of multiple ingestions of paracetamol occurring within a 24 hour period should be treated if the history of ingestion is greater than 200 mg/kg body weight or 10g (whichever is less) in the 24 hour period. If multiple / staggered ingestion has occurred over a 48 hour or 72 hour (or longer) period then the thresholds fall to 150 mg/kg or 6g (whichever is less) and 100 mg/kg or 4g (whichever is less) respectively. The nomogram must not be used for these patients as it may seriously underestimate risk.
Ingestion of modified release paracetamol
N-acetylcysteine should be commenced immediately in patients who ingest greater than 200 mg/kg body weight or 10g (whichever is less) of modified release paracetamol. Patients with a reported ingestion less than these amounts do not require immediate commencement of NAC unless a paracetamol concentration will not be determined within 8 hours of reported time of ingestion, or if the ingestion occurred greater than 8 hours previously. A plasma paracetamol concentration is determined 4 hours post ingestion (or as soon as possible if presenting greater than 4 hours post ingestion) and repeated 4 hours later. If the paracetamol concentration is below the treatment line, but increasing then N-acetylcysteine should be continued and another paracetamol concentration determined 2-4 hours later. N-acetlycysteine can be discontinued if the all paracetamol concentrations are below the treatment line and falling. Otherwise N-acetylcysteine is continued and management proceeds as per the Australasian staggered / supra-therapeutic ingestion treatment flow-chart.
In massive ingestions (>50g) of modified release paracetamol prolonged sustained paracetamol plasma concentrations can occur due to the formation of a pharmacobezoar, and subsequent delayed gastrointestinal absorption. In these cases N-acetylcysteine should be commenced regardless of paracetamol concentrations and continued until plasma paracetamol concentration is undetectable.
In cases where N-acetylcysteine is not available, methionine may be used as an oral antidote. It also appears effective if started within 8-10 hours of exposure but may have more side effects than N-acetylcysteine. It can only be given orally and commonly produces nausea and persistent vomiting. The dose is 2.5 grams initially followed by three more 2.5 gram doses at 4 hour intervals to a total dose of 10 grams.
Anti-emetic agents (e.g. -setrons) may be necessary to ensure absorption of methionine in a vomiting patient. The effect of activated charcoal on methionine absorption is unclear but is potentially significant if administered within 1 hour of methionine.
There is no evidence to support methionine in late paracetamol poisoning but all other indications are as for N-acetylcysteine (above).
All patients should receive N-acetylcysteine.
The overall prognosis for most patients with paracetamol hepatotoxicity is good. Management requires good supportive care. See hepatic failure guidelines flow chart.
Liver transplantation criteria
Patients with liver damage who have signs of a poor prognosis should have consultation with or be referred to a specialist liver unit or a liver transplant unit. Patients who should be considered for liver transplantation are those fulfilling the O'Grady criteria with the modification of Bernal.
Transport of patients with grade 3 or grade 4 encephalopathy is life threatening. Therefore, patients whose prognosis is poor should be transferred as soon as possible.
A recent systematic review of prognostic indicators in paracetamol induced hepatotoxicity concluded that the O'Grady criteria are well validated with good prognostic accuracy. However the Bernal modification using serum lactate reduced the diagnostic odds ratio when applied in studies outside the Kings College clinical environment. (Craig 2010)
In addition, supportive care is directed at detecting and treating:
Hypoglycemia is due to hepatic failure. Some patients may have symptomatic hypoglycemia despite a low - normal blood sugar.
All patients with hepatotoxicity and CNS depression or seizures should receive an intravenous bolus of 50% glucose regardless of their blood sugar.
Treatment of hepatic encephalopathy includes specific interventions and regular assessment.
Prolonged prothrombin time
An early rise (in the first 15 hours) in the prothrombin time in the absence of a transaminase rise is a transitory direct effect of paracetamol and not of prognostic importance. In the absence of bleeding, prothrombin times of less than 60 seconds do not require treatment. Patients with prothrombin times greater than 60-100 seconds should be referred to a specialist liver unit and considered for transplant.
This is due to acute tubular necrosis, although this may be compounded by hepatic failure. The treatment of renal failure in this setting is no different from acute tubular necrosis from any other cause. The prognosis of the renal function is good if the patient's liver function improves.
The prognosis for paracetamol poisonings who present to hospital is very good. Patients treated within 8 hours may be medically discharged as soon as treatment with N-acetylcysteine has ceased.
Patients who present greater than 8 hours after ingestion can be discharged if their transaminases are normal 24 hours following the ingestion.
Patients who develop hepatotoxicity have a mortality of less than 10% with good supportive care.
No long-term follow up is required after recovery but patients should probably be advised to avoid alcohol and other hepatic insults for a further month or two.
The html version of the 2008 Australian guideline can be found here
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