Pharmacology & Poisoning
A 54 year old man presents to the Emergency Department following an accidental overdose of paracetamol, taken for dental pain. His LFTs are deranged and the n-acetylcysteine (NAC) infusion is initiated. After approximately 30 minutes the patient becomes flushed and tachycardic. How should this situation be managed in the first instance?
Answer:
Clinically significant anaphylactoid reactions to intravenous acetylcysteine occur in up to 30% of patients treated with the standard 21-hour regimen, usually during or soon after the first infusion, when large amounts are given rapidly. Reactions can often be controlled by simply stopping the infusion temporarily. Consider giving chlorphenamine 10 mg IV and nebulised salbutamol 5 mg if bronchospasm is present. Once reaction has settled, restart the first bag at half the rate, then give the 2nd and 3rd bag at the normal rate.Paracetamol Toxicity
Pharmacology & Poisoning
Last Updated: 18th September 2024
Paracetamol is usually conjugated in the liver to inactive substances. A small amount is metabolised by the cytochrome P450 system producing a toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is then inactivated by conjugation with glutathione. In paracetamol overdose, the normal pathway of conjugation is saturated and a greater proportion of paracetamol is metabolised by the cytochrome P450 system. Once the reserves of glutathione are depleted, the toxic metabolite NAPQI builds up and causes hepatic necrosis.
All patients who meet any of the following criteria should be referred to hospital for medical assessment:
- Patients who have ingested paracetamol in the context of self-harm (irrespective of reported dose)
- Symptomatic patients
- Patients who have ingested 75 mg/kg or more paracetamol over a period of one hour or less
- Patients where the time of ingestion is uncertain but the dose ingested is 75 mg/kg or more
Clinical features
- Common: nausea and vomiting.
- Rarely: coma and severe metabolic acidosis in patients who have very high plasma paracetamol concentrations (greater than 700 mg/L).
- Later features in severe cases (12-36 hours): abdominal pain.
- After 2-3 days: features of hepatic necrosis with right subcostal pain and tenderness, nausea, vomiting, jaundice, acute kidney injury and hepatic encephalopathy.
- Loin pain, haematuria and proteinuria after the first 24 hours may indicate acute kidney injury.
- Clotting abnormalities increase the risk of bleeding from procedures such as surgery and tooth extraction.
Initial assessment
Calculate ingested dose in mg/kg to work out if significant ingestion:
- Disregard any additional kilos in excess of 110 kg
- If pregnant, enter pre-pregnancy, not actual weight
- All paracetamol ingestions ≥ 75 mg/kg/24hrs are significant
- If ingestion ≤ 1 h ago AND dose ≥ 150 mg/kg:
- Consider administration of single dose activated charcoal (50 g for adults; 1 g/kg body weight for children)
- Delay blood sampling until 4 h post-ingestion
- After 4 h, obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC) and await results
- If single ingestion > 1 h but < 4 h ago:
- Delay blood sampling until 4 h post-ingestion
- After 4 h, obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC) and await results
- If single ingestion ≥ 4 h but < 8 h ago...
- And it will be possible to act on blood results within 8 h of ingestion:
- Immediately obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC) and await results
- And it will not be possible to act on blood results within 8 h of ingestion AND dose ≥ 150 mg/kg:
- Immediately start NAC and obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC)
- And it will be possible to act on blood results within 8 h of ingestion:
- If single ingestion 8 - 24 h ago...
- And dose is < 150 mg/kg and they are asymptomatic
- Immediately obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC) and await results
- And dose is ≥ 150 mg/kg or they are symptomatic with jaundice or hepatic tenderness
- Immediately start NAC and obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC)
- And dose is < 150 mg/kg and they are asymptomatic
- If single ingestion > 24 h ago:
- And dose is < 150 mg/kg and they are asymptomatic
- Immediately obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC) and await results
- And dose is ≥ 150 mg/kg or they are symptomatic with jaundice or hepatic tenderness
- Immediately start NAC and obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC)
- And dose is < 150 mg/kg and they are asymptomatic
- If ingestion is staggered (ingestion over longer than 1 h):
- Immediately start NAC and obtain venous blood sample (plasma paracetamol level, U&Es, bicarbonate, glucose, LFTs, INR and FBC) (if necessary, delay blood sampling to ensure that 4 h has passed since last paracetamol ingestion)
Management based on blood results
NAC treatment required
Start or continue NAC if any of the following are true (if possible, within 8h of ingestion):
- 4 - 24 h after single ingestion, paracetamol level is on or above the treatment line
- >24 h after single ingestion, paracetamol is still detectable, ALT is above the upper limit of normal or INR > 1.3 (in the absence of another cause, e.g. warfarin)
- >4 h after last ingestion in a staggered ingestion, paracetamol is detectable
(N.B. The level of detection of paracetamol is 10 mg/L.)
N.B. If the patient has biochemical tests suggesting acute liver injury (e.g. ALT above the upper limit of normal) give acetylcysteine even if the plasma paracetamol concentration is below the at risk line on the nomogram. In cases of severe poisoning the ALT rises rapidly and is commonly abnormal at first presentation to hospital. A raised ALT may also indicate that the overdose was taken earlier than suggested by the history. Patients with a chronically elevated ALT (e.g. chronic liver disease) may not require acetylcysteine treatment if the ALT and INR have not significantly changed from previously documented values. These cases should be discussed with the NPIS.
Enhanced elimination using renal replacement therapy may be indicated in addition to acetylcysteine if a patient has very high paracetamol concentrations (greater than 700 mg/L) associated with coma and elevated blood lactate concentrations. Intermittent HD is the preferred modality for enhanced elimination. Continuous renal replacement modalities are valid alternatives if intermittent HD is not available. For patients on renal replacement therapy the dose of acetylcysteine (both regimens) should be doubled.
NAC treatment not required
NAC is not required or can be discontinued if:
- Paracetamol level is:
- below the treatment line at 4 - 24 h post-ingestion
- undetectable > 24 h after single ingestion OR
- undetectable > 4 h after last ingestion in staggered ingestion or ingestion of uncertain timing
- AND:
- ALT is within normal range
- INR ≤ 1.3
- Patient has no symptoms suggestive of liver injury
Standard 21-hour NAC regime
N-Acetylcysteine (NAC) ampoules contain 2 g NAC in 10 mL (200 mg/mL).
The NAC regime consists of 3 infusions given consecutively over 21 h:
- The dose of NAC for the first infusion is 150 mg/kg. For the first infusion add the required amount of NAC to a 200 mL bag of fluid, which should be infused over 1 h.
- For the next infusion, the dose of NAC is 50 mg/kg; add the required amount of NAC to a 500 mL bag of fluid, which should be infused over 4 h.
- For the last infusion; the dose of NAC is 100 mg/kg; add the required amount of NAC to a 1 L bag of fluid, which should be infused over 16 h.
| Infusion | NAC dose | Infusion fluid | Duration |
|---|---|---|---|
| 1 | 150 mg/kg | 200 mL | 1 h |
| 2 | 50 mg/kg | 500 mL | 4 h |
| 3 | 100 mg/kg | 1000 mL | 16 h |
Re-check the INR, plasma creatinine and ALT at, or just before, the end of the 21 hours of infusion. Paracetamol concentration should only be re-checked at the end of the 21 hour infusion if a large overdose was ingested. If re-checked continue NAC therapy if the paracetamol concentration is above the therapeutic range i.e. 20 mg/L or more. In patients with severe liver toxicity, also check lactate, venous pH or plasma bicarbonate.
Acetylcysteine treatment may be stopped if the blood results meet the following criteria:
- INR is 1.3 or less, AND
- ALT is within the normal range
- If the ALT is above the normal range (with an INR of 1.3 or less), acetylcysteine may still be stopped if:
- ALT is less than two times the upper limit of normal AND
- The increase in ALT value is not more than a doubling of the admission value
Acetylcysteine should be continued if blood results are abnormal and meet ANY of the following criteria:
- the ALT is more than two times the upper limit of normal OR
- the ALT has doubled or more since the admission measurement AND is above the upper limit of normal OR
- the INR is greater than 1.3 (in the absence of another cause e.g. warfarin) AND the ALT is above the upper limit of normal OR
- the INR has risen by 0.5 or more from the admission measurement
If acetylcysteine is to be continued, continue at the dose and infusion rate used in the 3rd treatment bag. It is not necessary to give a further loading dose unless a second overdose has been taken. Repeat all blood tests in a further 8-16 hours.
Modified 12-h NAC regime (SNAP)
The Scottish and Newcastle Acetylcysteine Protocol (SNAP) regimen for IV acetylcysteine can be used as an alternative to the above.
- First infusion: Add the appropriate volume of acetylcysteine (100 mg/kg body weight, maximum 11 g) to 200 mL 5% glucose or 0.9% sodium chloride, infused over 2 hours.
- Second infusion: Add the appropriate volume of acetylcysteine (200 mg/kg body weight, maximum 22 g) to 1000 mL 5% glucose or 0.9% sodium chloride and infuse over the next 10 hours.
In all patients re-check the plasma paracetamol concentration, INR, creatinine, venous pH or plasma bicarbonate and ALT at the end of the 2nd treatment bag (12-hour infusion).
If all blood results are normal, the patient can be considered for discharge:
- INR is 1.3 or less AND
- ALT is within the normal range AND
- Paracetamol concentration is less than 10 mg/L AND
- Patient has no symptoms suggesting liver damage.
If blood results are abnormal, continue acetylcysteine at the dose and infusion rate used in the 2nd treatment bag:
- The ALT is increased above the upper limit of the normal range, OR
- the INR is greater than 1.3 (in the absence of another cause, e.g. warfarin), OR
- the paracetamol concentration is greater than 10 mg/L
NAC adverse reactions
Clinically significant anaphylactoid reactions to intravenous acetylcysteine occur in up to 30% of patients treated with the standard 21-hour regimen, usually during or soon after the first infusion, when large amounts are given rapidly. They are more common in women, people with asthma or atopy, those with family history of allergies, and patients with low paracetamol levels.
Features may include:
- Nausea
- Vomiting
- Flushing
- Urticarial rash
- Angioedema
- Tachycardia
- Bronchospasm
- Hypotension
- Shock
A history of anaphylactoid reactions is NOT a contraindication to intravenous acetylcysteine in patients with paracetamol overdose when antidote treatment is clinically indicated.
Management:
- Reactions can often be controlled by simply stopping the infusion temporarily.
- Consider giving chlorphenamine 10 mg IV and nebulised salbutamol 5 mg if bronchospasm is present.
- It is essential that the acetylcysteine infusion is restarted once the reaction has settled. Consider slowing the infusion rate (e.g. administer the first bag over twice as long as usual. The normal infusion rate can be used for subsequent bags).
Previous reaction is NOT a contraindication to NAC, but consider pre-treatment with chlorphenamine 10 mg IV, ranitidine 50 mg IV and salbutamol 5 mg neb. Consider using the modified 12-hour IV acetylcysteine regimen (known as the Scottish and Newcastle Acetylcysteine Protocol; SNAP). The total dose of intravenous acetylcysteine is the same as the standard 21-hour regimen (i.e. 300 mg/kg) but the rate and duration of treatment is different which results in a lower peak plasma acetylcysteine concentration and a significantly reduced risk of anaphylactoid reactions.
Referral for liver transplant
The King's College Criteria (KCC) are a well-accepted criteria that show the degree of multiorgan dysfunction from paracetamol-induced liver failure. Used alone or with serum lactate and phosphate, the KCC can predict patients with poor prognosis, and select patients most likely to benefit from immediate liver transplant referral.
- Arterial pH < 7.30
- INR > 6.5 (PT > 100 sec)
- Creatinine 3.4 mg/dL (300 µmol/L)
- Grade III or IV hepatic encephalopathy
+/-
- Lactate > 3.5 mmol/L after fluid resuscitation (<4 hrs) OR lactate > 3 mmol/L after full fluid resuscitation (12 hours)
- Phosphate > 3.75 mg/dL (1.2 mmol/L) at 48-96 hours
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
