Assessment and management of paracetamol poisoning in adults

Assessment

Patients who overdose on paracetamol may present to hospital following a single acute overdose (ingestion within one hour), a staggered overdose (repeated ingestions over more than one hour) or therapeutic excess (accidental ingestion of a potentially toxic dose during clinical use). As with any emergency admission, immediate assessment should include:

• Airway.
• Breathing.
• Circulation.

A patient who presents to hospital quickly following a paracetamol-only overdose will usually be clinically stable and have few, if any, symptoms. However, many patients who overdose co-ingest other drugs or alcohol, which may give rise to a variety of clinical features at presentation. In addition, some patients may be emotionally distressed, can be expressing suicidal thoughts or have a psychiatric disorder. It is not within the remit of this module to discuss all aspects of care in these circumstances, and the main focus will be on assessment and management of paracetamol toxicity.

Assessment and management of paracetamol poisoning is complex and guidance is available free to NHS healthcare professionals from the NPIS in the UK. The NPIS provides an up-to-date online database called TOXBASE (www.toxbase.org), and if further information is required, it can be obtained via the 24-hour NPIS telephone line (0844 892 0111). This service is staffed by scientists qualified in poisons information and is supported by a consultant clinical toxicologist rota.

Box 1. Paracetamol overdose: simplification of the use of intravenous acetylcysteine

The Commission on Human Medicines reviewed the use of acetylcysteine for the treatment of paracetamol overdose and made the following recommendations (Medicines and Healthcare products Regulatory Agency 2012):

• The licence indication for acetylcysteine is now:
  • Administer acetylcysteine irrespective of the plasma paracetamol concentration in circumstances where the overdose is staggered or where there is doubt about the time of ingestion.
  • Administer acetylcysteine with a timed plasma concentration on or above a single treatment line regardless of risk factors of hepatotoxicity.
• The use of weight-based acetylcysteine dosing tables for adults and children.
• An increase in duration of the first dose of intravenous acetylcysteine from 15 minutes to one hour.
• Removal of hypersensitivity as a contraindication to treatment with acetylcysteine.
• Inclusion of a technical information leaflet in every pack of acetylcysteine, which gives instructions on the preparation of acetylcysteine infusions.

Review by Commission on Human Medicines (CHM)

In the UK assessment and management of paracetamol poisoning changed following a review by the Commission on Human Medicines (CHM) (Medicines and Healthcare products Regulatory Agency (MHRA) 2012). Historically, a nomogram with two treatment lines together with individual risk factors were used to assess the risk of toxicity (BNF 2012). Although there is evidence suggesting that factors such as chronic alcohol consumption (Zimmerman and Maddrey 1995), starvation (Whitcomb and Block 1994) and use of enzyme-inducing drugs (BNF 2015/2016) may increase the risk of hepatotoxicity, the CHM has advised that these should no longer be used in the assessment of paracetamol toxicity.

Safety warning by MHRA

Following the CHM review, the MHRA published a safety warning on September 3 2012 to simplify treatment decisions following a paracetamol overdose (Box 1). The principal recommendations were to administer acetylcysteine, irrespective of plasma paracetamol concentration, to patients following a staggered overdose and to treat patients whose timed paracetamol concentrations are on or above a single treatment line nomogram (Figure 2), regardless of risk factors (MHRA 2012). Following the recommendations of the CHM and after discussion with the MHRA, the NPIS has responded by changing guidance on TOXBASE.

Figure 2. Paracetamol treatment line nomogram

History collection

On presentation to hospital, it is important to take an accurate history from the patient to establish the amount of paracetamol ingested, time of ingestion and whether ingestion was a single acute overdose or a staggered overdose (Ferner et al 2011). A timed plasma paracetamol concentration plotted on the paracetamol treatment line nomogram (Figure 2) is the most effective way of assessing risk of toxicity. However, the nomogram can only be used where the overdose is a single ingestion and presentation is within 24 hours.

Assessment of paracetamol poisoning using the information from TOXBASE is based on the interval between ingestion and presentation to hospital. To deliver effective care, nurses should have a good understanding of the appropriate management of paracetamol poisoning at different time intervals from ingestion.

Laboratory investigations

When a patient presents to hospital less than eight hours after a single acute overdose, urgent laboratory blood samples should be obtained at least four hours after ingestion for paracetamol concentration, urea and electrolytes (U&Es), creatinine, bicarbonate, LFTs, INR and full blood count (FBC). There is no benefit in requesting a paracetamol concentration before four hours as the result cannot be interpreted because absorption is not complete. A paracetamol concentration plotted on or above the paracetamol treatment line nomogram indicates the patient is at risk of hepatotoxicity and antidotal therapy is indicated. Other blood tests provide a baseline of liver and renal function and at this time should be within the normal range, unless the patient has other underlying health problems.

Assessment of acute overdose

When presentation is between eight and 24 hours after a single acute ingestion, assessment of risk is initially determined by the history of the amount of paracetamol ingested. Antidotal therapy should commence without delay if more than 150mg/kg has been ingested, even if the paracetamol concentration is not yet available (TOXBASE 2013). For patients weighing more than 110kg, the mg/kg dose of paracetamol ingested should be calculated using 110kg rather than the patient’s actual weight and if the patient is pregnant, the mg/kg dose should be calculated using pre-pregnancy weight (TOXBASE 2013).

The effectiveness of the antidote declines rapidly at this time, so waiting for blood results may be detrimental. Healthcare professionals are often concerned about administering acetylcysteine before paracetamol concentration is available (Thanacoody et al 2008), but should be reassured that patient history of the amount of paracetamol ingested tends to be reliable (Waring et al 2008a).

Blood sampling is the same as for the less than eight-hour presentation and, when the plasma paracetamol concentration is available, the need for continuation of antidotal therapy can be reassessed using the paracetamol nomogram. If the paracetamol concentration is below the treatment line, acetylcysteine can be discontinued provided that the patient is asymptomatic, the ALT and INR are normal, and there is no doubt about the timing of ingestion (TOXBASE 2013).

When presentation is more than 24 hours after a single acute ingestion, blood sampling is the same as for eight to 24 hours, but additional samples should include a blood glucose concentration and venous blood gas. Guidelines advise waiting for blood results before commencing treatment with acetylcysteine, unless the patient is clearly jaundiced or has hepatic tenderness (TOXBASE 2013). Once blood results are available the need for treatment can be assessed fully.

A measurable paracetamol concentration (5mg/L or more) at this time indicates a large overdose, a mistake in the time of ingestion or possibly a staggered overdose, and a full course of acetylcysteine should usually be administered. An abnormal ALT and a raised INRstrongly suggest paracetamol toxicity and treatment with acetylcysteine is recommended. Delayed presentation after 24 hours is more likely to be associated with poor outcome in paracetamol-induced acute liver failure (Craig et al 2012), and these patients should be treated with acetylcysteine if they are considered to be at risk of liver damage (TOXBASE 2013).

Assessment of staggered overdose

Patients who present to hospital following a staggered overdose require careful assessment and expert advice from the NPIS may be required. A recent study of patients admitted to a liver transplant unit suggests that severe liver injury following a staggered overdose is associated with reduced survival (Craig et al 2012). Risk assessment is based on the presence or absence of features of paracetamol toxicity, history of the dose ingested, timing of the ingestions and results of blood tests. Initial blood tests should include paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC.

The CHM recommends that treatment with acetylcysteine should be administered to patients who have taken a staggered overdose (MHRA 2012). The NPIS has developed management advice following the CHM review and discussion with the MHRA (TOXBASE 2013). Serious toxicity may occur where patients have ingested more than 150mg/kg within any 24-hour period; toxicity is rare in patients who have ingested 75mg/kg to 150mg/kg in any 24-hour period; and doses less than 75mg/kg in 24 hours are unlikely to be toxic.

Ingestion of a licensed dose of 4g in 24 hours by an adult is not considered to be an overdose. Significant toxicity is unlikely if 24 hours after the last paracetamol ingestion all the following criteria are met: the paracetamol concentration is less than 5mg/L; the INR is 1.3 or less; the ALT is less than 100IU/L; the creatinine is normal; and the patient is asymptomatic.

Assessment of therapeutic excess

Definition

Therapeutic excess is defined as ingestion of more than the daily licensed dose of paracetamol (4g) and more than or equal to 75mg/kg in any 24-hour period.

Patients presenting with therapeutic excess require careful assessment using history of dose, time of ingestion, clinical features (if present) and blood results.

Following the CHM review, the NPIS advice is that where ingestion is 150mg/kg or more, the patient should be treated (TOXBASE 2013). Clinical judgement is required when assessing ingestion between 75mg/kg and 150mg/kg in any 24-hour period. Factors to be taken into account are:

• Magnitude of exposure.
• Length of time exposed.
• Patient’s intent.

Blood tests should include paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC.

Learning Points

1. Patients who overdose on paracetamol may present to hospital following a single acute overdose (ingestion within one hour), a staggered overdose (repeated ingestions over more than one hour) or therapeutic excess (accidental ingestion of a potentially toxic dose during clinical use).
2. When a patient presents to hospital less than eight hours after a single acute overdose, urgent laboratory blood samples should be obtained at least four hours after ingestion for paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC.
3. When presentation is between eight and 24 hours after a single acute ingestion, assessment of risk is initially determined by the history of the amount of paracetamol ingested. Antidotal therapy should commence without delay if more than 150mg/kg has been ingested, even if the paracetamol concentration is not yet available.
4. When presentation is more than 24 hours after a single acute ingestion, blood sampling is the same as for eight to 24 hours, but additional samples should include a blood glucose concentration and venous blood gas.
5. Delayed presentation after 24 hours is more likely to be associated with poor outcome in paracetamol-induced acute liver failure, and these patients should be treated with acetylcysteine if they are considered to be at risk of liver damage.
6. Patients who present to hospital following a staggered overdose require careful assessment. Risk assessment is based on the presence or absence of features of paracetamol toxicity, history of the dose ingested, timing of the ingestions and results of blood tests.
7. Therapeutic excess is defined as ingestion of more than the daily licensed dose of paracetamol (4g) and more than or equal to 75mg/kg in any 24-hour period.

Management

Activated charcoal: treatment of patients with paracetamol poisoning is aimed at reducing the amount of paracetamol absorbed from the gastrointestinal tract and replacing glutathione stores. Oral activated charcoal can decrease absorption of paracetamol, if administered within one hour of ingestion (Green et al 2001). Activated charcoal is a black liquid preparation and the recommended dose is 50g (250mL) for an adult (BNF 2015/2016). Many patients find charcoal unpalatable and difficult to take, but if tolerated it can reduce the need for antidotal therapy (Buckley et al 1999).

Acetylcysteine: the antidote acetylcysteine acts as a precursor for glutathione to assist the regeneration of supplies and promote normal conjugation of paracetamol. For maximum effect, administration of intravenous acetylcysteine should commence within eight hours of ingestion (Prescott et al 1979, Ferner et al 2011, TOXBASE 2013, BNF 2015/2016), although it still has benefit if given later than this. Acetylcysteine has been shown to decrease mortality in patients with established liver failure (Mehrpour et al 2010).

Acetylcysteine dose is based on the patient’s body weight and requires administration of three infusions over a period of 21 hours. Each infusion contains a different dose of acetylcysteine, diluted in a different volume of glucose 5% (sodium chloride 0.9% can be used if glucose is unsuitable) and each infusion is administered at a different rate (BNF 2015/2016). In addition, the CHM recommends using a weight-based dosing table (Table 1) when prescribing acetylcysteine, to simplify the use of intravenous acetylcysteine (MHRA 2012). The duration of the first infusion has also been extended from 15 minutes to one hour.

Table 1 - Adult acetylcysteine dosing table

Adult acetylcysteine prescription (each ampoule = 200mg/mL acetylcysteine)
Regimen	First infusion		Second infusion		Third infusion
Infusion fluid	200mL glucose 5% or sodium chloide 0.9%		500mL glucose 5% or sodium chloide 0.9%		1,000mL glucose 5% or sodium chloide 0.9%
Duration of infusion	1 hour		4 hours		16 hours
Drug dose	150mg/kg acetylcysteine		50mg/kg acetylcysteine		100mg/kg acetylcysteine
Patient weight*	Ampoule volume†	Infusion rate	Ampoule volume†	Infusion rate	Ampoule volume†	Infusion rate
kg	mL	mL/hour	mL	mL/hour	mL	mL/hour
40-49	34	234	12	128	23	64
50-59	42	242	14	129	28	64
60-69	49	249	17	129	33	65
70-79	57	257	19	130	38	65
80-89	64	264	22	131	43	65
90-99	72	272	24	131	48	66
100-109	79	279	27	132	53	66
≥110	83	283	28	132	55	66
* Dose calculations are based on the weight in the middle of each band.
If the patient weighs less than 40kg, use the paediatric dose table on TOXBASE. † Ampoule volume has been rounded up to the nearest whole number.
(Medicines and Healthcare products Regulatory Agency 2012, TOXBASE 2013)

Many nurses in emergency departments and acute medical assessment units are skilled in history taking and competent in venepuncture. Therefore, if they are aware of the importance of prompt and accurate assessment of patients presenting with paracetamol poisoning, they are in a good position to triage and prioritise care appropriately. A summary of the key points of assessment and management at specific time intervals following ingestion of paracetamol is shown in Table 2.

Table 2 - 

 Key points of assessment and management at specific times following ingestion of paracetamol

Presentation	Key points
Less than 8 hours after ingestion	Administer oral activated charcoal if the patient has ingested more than 150mg/kg of paracetamol and presentation is within one hour of ingestion. Obtain urgent blood samples for paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC at least four hours after ingestion. Assess the need for acetylcysteine using the single treatment line nomogram, providing a paracetamol concentration can be obtained and acted on within eight hours of ingestion.
8-24 hours after ingestion	Obtain urgent blood samples for paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC. Administer acetylcysteine immediately if the patient has ingested more than 150mg/kg. Do not wait for blood results. Reassess need for acetylcysteine when blood results are available.
Over 24 hours after ingestion	Obtain urgent blood samples for paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR, FBC and glucose. Obtain a venous blood gas sample. Administer acetylcysteine immediately if the patient is jaundiced or has hepatic tenderness. Reassess the need for acetylcysteine when blood results are available.
Staggered ingestion	Obtain urgent blood samples for paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC. Administer acetylcysteine immediately if the patient is jaundiced or has hepatic tenderness. Administer acetylcysteine if the patient has ingested more than 75mg/kg of paracetamol. Administer acetylcysteine if alanine aminotransferase (ALT) or INR are abnormal. Administer acetylcysteine if paracetamol concentration is detectable (5mg/L or more).
Therapeutic excess	Obtain urgent blood samples for paracetamol concentration, U&Es, creatinine, bicarbonate, LFTs, INR and FBC. Administer acetylcysteine immediately if the patient is jaundiced or has hepatic tenderness. Administer acetylcysteine if the patient has ingested more than 150mg/kg of paracetamol. Administer acetylcysteine if ALT or INR are abnormal. Administer acetylcysteine if paracetamol concentration is detectable (5mg/L or more) 24 hours after the last dose. Clinical judgement is required where patients have ingested 75-150mg/kg of paracetamol.
U&Es – urea and electrolytes; LFTs – liver function tests; FBC – full blood count; INR – international normalised ratio
(TOXBASE 2013, British National Formulary 2015/2016) Learning Points :

1. Treatment of patients with paracetamol poisoning is aimed at reducing the amount of paracetamol absorbed from the gastrointestinal tract and replacing glutathione stores.
2. Activated charcoal is a black liquid preparation and the recommended dose is 50g (250mL) for an adult. Many patients find charcoal unpalatable and difficult to take, but if tolerated it can reduce the need for antidotal therapy.
3. The antidote acetylcysteine acts as a precursor for glutathione to assist the regeneration of supplies and promote normal conjugation of paracetamol.
4. For maximum effect, administration of intravenous acetylcysteine should commence within eight hours of ingestion, although it still has benefit if given later than this. Acetylcysteine has been shown to decrease mortality in patients with established liver failure.
5. Acetylcysteine dose is based on the patient’s body weight and requires administration of three infusions over a period of 21 hours. Each infusion contains a different dose of acetylcysteine, diluted in a different volume of glucose 5% (sodium chloride 0.9% can be used if glucose is unsuitable) and each infusion is administered at a different rate.

Adverse reactions to acetylcysteine

Administration of intravenous acetylcysteine can cause an anaphylactoid reaction (Pakravan et al 2008, Sandilands and Bateman 2009), usually within the first 30 minutes of administration, when concentrations are highest. Nausea, vomiting, flushing, rash, bronchospasm and tachycardia are common features, with hypotension and collapse occurring rarely (Figure 3). Adverse reactions are more likely to occur in patients with a low paracetamol concentration (Waring et al 2008b). Patients with asthma, those with family history of drug allergies and women appear to be more susceptible to adverse reactions (Sandilands and Bateman 2009).

Most reactions can be treated by suspending the infusion for a short time until symptoms have subsided. Administration of an antihistamine (chlorphenamine) for rash, an anti-emetic (cyclizine) for vomiting and a nebulised short-acting beta-2-agonist (salbutamol) for bronchospasm may be required (TOXBASE 2013). Once the reaction has subsided, the full course of the antidote can be completed, perhaps at a slower rate.

Following the CHM review, the administration of the first dose of acetylcysteine has increased in duration from 15 minutes to one hour (MHRA 2012). This increase in duration may change the frequency and time of adverse drug reactions.

Figure 3. Adverse reactions to acetylcysteine

End of treatment and discharge

Once the full course of acetylcysteine is complete, blood tests to assess liver and renal function are required. Blood sampling for INR, LFTs (ALT), creatinine and U&Es (plasma bicarbonate) are obtained. If the results are all normal, the patient can be discharged from hospital with advice to seek medical help if abdominal pain or vomiting develops. The MHRA (2012) recommends giving the patient an information sheet on discharge. Information sheets are available from the TOXBASE or MHRA website.

A patient who has abnormal blood results indicating the onset of liver injury, should remain in hospital for further treatment with acetylcysteine and monitoring of liver function. Further guidance on the interpretation of these blood results is available on TOXBASE. Abnormal renal function at the end of the full course of acetylcysteine should be monitored and treated conventionally (TOXBASE 2013).

Patients who deliberately overdose usually require psychological assessment and local arrangements for this service will apply.

Learning Points 

1. Administration of intravenous acetylcysteine can cause an anaphylactoid reaction usually within the first 30 minutes of administration, when concentrations are highest.
2. Nausea, vomiting, flushing, rash, bronchospasm and tachycardia are common features, with hypotension and collapse occurring rarely. Most reactions can be treated by suspending the infusion for a short time until symptoms have subsided.
3. Adverse reactions are more likely to occur in patients with a low paracetamol concentration. Patients with asthma, those with family history of drug allergies and women appear to be more susceptible to adverse reactions.
4. Administration of an antihistamine (chlorphenamine) for rash, an anti-emetic (cyclizine) for vomiting and a nebulised short-acting beta-2-agonist (salbutamol) for bronchospasm may be required.
5. Once the full course of acetylcysteine is complete, blood tests to assess liver and renal function are required. Blood sampling for INR, LFTs (ALT), creatinine and U&Es (plasma bicarbonate) are obtained.

Conclusions

• Paracetamol remains the most common product taken in overdose.
• Study findings following the introduction of strategies to reduce the incidence and severity of paracetamol poisoning in the UK (such as pack size changes) are inconclusive.
• Management of paracetamol poisoning is complex, and in September 2012 the MHRA published a safety warning to simplify treatment decisions following a paracetamol overdose. Nurses can play an important role in the assessment and management of patients who overdose.
• Please note, the information in this module was correct at the time of publication, however advice on paracetamol poisoning may change at any time. Readers should be aware that up-to-date advice on paracetamol poisoning can be accessed from TOXBASE.

Acronyms

ALT: alanine aminotransferase

BNF: British National Formulary

CHM: Commission on Human Medicines

FBC: full blood count

GP: general practitioner

INR: international normalised ratio

LFTs: liver function tests

MHRA: Medicines and Healthcare products Regulatory Agency

NAPQI: N-acetyl-p-benzoquinoneimine

NHS: National Health Service

NPIS: National Poisons Information Service

NSAID: non-steroidal anti-inflammatory drug

TOXBASE: toxicology database

U&E: urea and electrolytes

Glossary

Anaphylactoid reaction: an acute allergic response in which the body releases histamine.

Asthma: a chronic inflammation of the airways associated with widespread, variable airflow obstruction. Symptoms include wheezing, coughing, breathing difficulties and chest tightness. Asthma may be reversible with appropriate treatment, but left untreated it can be life-threatening.

Bronchospasm: extreme and long drawn-out contraction of the smooth muscle of the bronchi and bronchioles, which leads to acute narrowing and obstruction of the airway.

Hepatotoxicity: the tendency of an agent, usually a drug or alcohol, to have a destructive effect on the liver.

Hypoglycaemia: an abnormally low level of glucose in the blood, defined as less than 4 mmols/L. It is characterised by nausea, headache, perspiration, anxiety, confusion and altered consciousness.

Hypotension: when the blood pressure is not adequate for perfusion and oxygenation of the tissues. This abnormal condition may be caused by diminished heart output or an expanded intravascular space.

Metabolic acidosis: when excess acid is added to the body fluids or bicarbonate is lost from them. Acidosis occurs in blood with a pH of under 7.4.

Non-steroidal anti-inflammatory drug (NSAID): analgesic medication that works to decrease blood levels of prostaglandins, chemicals that promote inflammation and pain. Effective for the reduction of pain, fever and inflammation.

Over-the-counter medicine: a drug sold without a prescription.

Tachycardia: a heart rate greater than 100 beats per minute.

Toxicity: a condition that results from exposure to a toxin or to toxic amounts of a substance that does not cause adverse effects in smaller amounts.

References

British National Formulary (2012) British National Formulary No. 63. BMJ Group and Royal Pharmaceutical Society of Great Britain, London.

British National Formulary (2015/2016) British National Formulary No. 70. BMJ Group and Royal Pharmaceutical Society of Great Britain, London.

Buckley NA, Whyte IM, O’Connell DL, Dawson AH (1999) Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. Journal of Toxicology. 37, 6, 753-757. MEDLINE

Chandrasekharan NV, Dai H, Roos KL et al (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proceedings of the National Academy of Sciences of the United States of America. 99, 21, 13926-13931. MEDLINE • CROSSREF

Craig DG, Bates CM, Davidson JS, Martin KG, Hayes PC, Simpson KJ (2012) Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity. British Journal of Clinical Pharmacology. 73, 2, 285-294. MEDLINE • CROSSREF

Ferner RE, Dear JW, Bateman DN (2011) Management of paracetamol poisoning. British Medical Journal. 342, d2218. MEDLINE •CROSSREF

Green R, Grierson R, Sitar DS, Tenenbein M (2001) How long after drug ingestion is activated charcoal still effective? Journal of Toxicology. 39, 6, 601-605. MEDLINE