Paracetamol (acetaminophen)

Paracetamol is a readily available analgesic and is commonly taken in overdose. It is available in immediate and slow-release preparations as well as in combination products often containing opioids, caffeine or ibuprofen. Several strengths of liquid paracetamol are also available.

Excess paracetamol ingestion results in the accumulation of a toxic intermediate metabolite N-acetyl-p-benzoquinonimine (NAPQI). Untreated paracetamol toxicity can be fatal and is characterised by hepatotoxicity which can progress to fulminant hepatic failure.

Fortunately, an effective antidote, N-acetylcysteine (NAC), is readily available and treatment within 8 hours of ingestion should prevent serious hepatic toxicity.

In therapeutic use, 20% of an ingested dose of paracetamol undergoes first pass metabolism, with further metabolism occurring in the liver by biotransformation. The majority (90%) is metabolised to sulphate and glucuronide conjugates that are excreted in the urine. The remainder (less than 10%) is metabolised via cytochrome p450 (mainly 2E1 and 3A4) resulting in the highly reactive intermediary compound NAPQI. Normally, NAPQI is immediately bound by intracellular glutathione and eliminated in the urine.

In overdose, glutathione stores are depleted, and NAPQI instead binds to sulfhydryl containing proteins in the liver cells and causes lipid peroxidation, disrupting the cell membrane. These events eventually lead to cell death. Any organ with P450 enzymes can suffer damage, particularly the liver and kidney, but the heart and pancreas can also be affected.

In massive ingestion with very high paracetamol concentrations (generally >600mg/L) patients can develop altered level of consciousness, including coma, and a lactic acidosis. This results from mitochondiral toxicity due to inhibition of the electron transport chain. This resolves as the paracetamol level reduced, but in some cases, if the acidosis is severe, dialysis may be required.

There are numerous guidelines published for the treatment of paracetamol related toxicity. The risk assessment and treatment outlines in this monograph are based on the Australian Guidelines for the Treatment of Paracetamol Toxicity ( add link) .

An accurate risk assessment is crucial in determining the need for investigation and treatment following overdose. Important information in the risk assessment includes:

• Dose ingested.
• Formulation (IR vs XR).
• Time of ingestion.
• If staggered or supratherapeutic use, the period over which the ingestion was taken.
• Serum paracetamol level (early).
• Clinical and laboratory features of acute liver injury (late).

Acute single ingestion of immediate release paracetamol

An acute single ingestion of paraetamol that may be associated with acute liver injury if defined as ≥10g or ≥200mg/kg (whichever is less).

For acute single dose ingestion of immediate release paracetamol with a known time of ingestion, the paracetamol treatment nomogram (Image 2) can be used to determine the need for NAC therapy.

The treatment guidelines for an acute single ingestion are shown in (Image 3). Multiple or staggered ingestions (over a period of more than 2hr) are distinct from repeated supratherapeutic ingestions and should be treated as per the single ingestion guideline (Box 3) using the earliest ingestion time for plotting on the nomogram.

For accidental ingestion of liquid paracetamol in children <;6yo then a paracetamol level can be taken 2 hours post ingestion, if it is <;150mg/L then no treatment is needed, if it is above 150mg/kg then a 4-hour level should be taken, NAC therapy is indicated if this level is 150mg/kg or higher.

Images 2-3. Click to enlarge

Modified releas e paracetamol ingestions

Modified release paracetamol ingestions were previously treated similarly to immediate release paracetamol ingestions however, evidence has shown that this approach is inadequate with some patients developing a liver injury despite following these guidelines.

Image 4 shows the treatment protocol for modified release paracetamol ingestions. Of note, all patients ingesting >10g of modified release paracetamol require at least a complete course of NAC.

Image 4. Click to enlarge.

Repeated Supratherapeutic paracetamol ingestion

A repeated supratherapeutic ingestion (RSTI) is defined as any of the following:

• ≥ 10g or ≥ 200mg/kg (whichever is less) over a 24hr period
• ≥ 12g or ≥ 300mg/kg (whichever is less) over a 48hr period
• ≥ a daily therapeutic dose per day for more than 48hr in pateints who also have abdominal pain or nausea or vomiting

Image 5. Click to enlarge.

Paracetamol is rapidly absorbed with peak concentrations within 1-2h for the standard tablet formulation and within 30 min for liquid preparations. Peak concentrations are delayed to over 12 hours and sometimes longer in slow-release preparations.

Prolonged absorption is seen following very large ingestions (>500mg/kg).

After absorption, paracetamol distributes rapidly with a volume of distribution of 0.9L/kg. Absorption and distribution are completed by 4 hours post overdose with standard release preparations and within 2 hours for liquid preparations.

Metabolism is mainly via glucuronidation and sulphation. Half-life in therapeutic use is 1.5-3 hours, however in overdose this can be delayed to more than 4 hours. A higher half-life has been linked to a higher risk of toxicity, which may indicate saturation of conjugation pathway and an increasing proportion of paracetamol being metabolised by P450 enzymes.

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 (>1000 U/L) is seen with significant toxicity. The extent and speed of ALT rise has been linked with subsequent severity.

Clinically patients may complain of nausea, anorexia and right upper quadrant tenderness. In severe toxicity hypoglycaemia, encephalopathy, jaundice and coagulopathy can develop.

Acute renal failure with acute tubular necrosis secondary to NAPQI, is usually reversible. It occurs in a small proportion of patients with hepatotoxicity. It can occur in some patients 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)]:

• Full blood count (baseline)
• Coagulation studies
• Electrolytes, creatinine
• Blood glucose monitoring
• Liver enzymes
• Phosphate
• Paracetamol concentrations

Conversion factor for paracetamol concentrations

• mg/L x 6.62 = mmol/L
• mmol/L x 0.151 = mg/L

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:

• a prothrombin time > 100 seconds (INR > 8) at any time
• a rising prothrombin time between days 3 and 4
• a prothrombin time in seconds which is greater than the number of hours post overdose (after 24 hours)
• Grade III or IV hepatic encephalopathy
• serum creatinine > 300 micromol/L or increasing creatinine
• metabolic acidosis (pH<7.3 despite fluid resuscitation) or a high lactate
• a rising phosphate

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:

• Dose ingested
• Paracetamol concentration (see nomogram)
• Clinical assessment of risk (in late presentations only)

The ingested dose is useful in risk assessment in the following clinical scenarios:

• In the absence of a paracetamol concentration
• When the time of ingestion is not known
• In controlled release preparations
• When patients have taken multiple doses within a 24 hour period

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.

Conversion factor

• mg/L x 6.62 = micromol/L
• micromol/L x 0.151 = mg/L

Nomogram

Table for SI units

Table for mass units

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:

• on the basis of their ingested dose (treat anyone with a total daily dose > 150 mg/kg, 200 mg/kg if exposure for 24 hours or less))
• by using a worst case analysis
• by determining the paracetamol half life

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.

Methods
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.

• Gastric lavage is not indicated.
• Repeated doses of activated charcoal are not useful.
• Whole bowel lavage should be considered in slow-release paracetamol ingestions.

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)

Adults

• 150 mg/kg in 200 mL of 5% Dextrose over 15-60 minutes then
• 50 mg/kg in 500 mL of 5% Dextrose over 4 hours then
• 50 mg/kg in 500 mL of 5% Dextrose over 8 hours then
• 50 mg/kg in 500 mL of 5% Dextrose over 8 hours.
• The total dose over 20-21 hours is 300 mg/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 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

• 150 mg/kg in 100 mL of 5% Dextrose over 15-60 minutes then
• 50 mg/kg in 250 mL of 5% Dextrose over 4 hours then
• 50 mg/kg in 250 mL of 5% Dextrose over 8 hours then
• 50 mg/kg in 250mL of 5% Dextrose over 8 hours.
• The total dose over 20-21 hours is 300 mg/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

• 150 mg/kg in 3 mL/kg of 5% Dextrose over 15-60 minutes then
• 50 mg/kg in 7 mL/kg of 5% Dextrose over 4 hours then
• 50 mg/kg in 7 mL/kg of 5% Dextrose over 8 hours then
• 50 mg/kg in 7 mL/kg of 5% Dextrose over 8 hours.
• The total dose over 20-21 hours is 300 mg/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.

O'Grady criteria

• Arterial blood pH < 7.3 after resuscitation

OR

• A prothrombin time greater than 100 seconds

and

• Serum creatinine > 300 mmol/L

and

• Patients with Grade III or Grade IV encephalopathy

Bernal modification

• Serum lactate > 3.0 mmol/L at 4 hours or > 3.5 mmol/L at 12 hours after admission to liver unit and fluid resuscitation

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
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.

• Ensure adequate continuous carbohydrate intake (oral or IV)
• Monitor blood glucose regularly (e.g 4th hourly)

Hepatic encephalopathy
Treatment of hepatic encephalopathy includes specific interventions and regular assessment.

• A low protein/high carbohydrate diet
• Lactulose 15-30 mL QID
• Regular monitoring of severity:
  • Constructional apraxia (star chart)
  • Handwriting chart
  • Sleep/awake chart
  • Hepatic flap

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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