Download Intravenous Acetylcysteine for Paracetamol Toxicity in Adults

Title of Guideline (must include the word “Guideline” (not protocol,
policy, procedure etc)
Trust Wide Intravenous
Acetylcysteine for Paracetamol
Toxicity in Adults Guideline
Author: Contact Name and Job Title
Directorate & Speciality
Gemma Warren,
Specialist Clinical PharmacistEmergency Department
Acute Medicine
Date of submission
February 2016
Explicit definition of patient group to which it applies (e.g. inclusion
and exclusion criteria, diagnosis)
Includes:
Adult patients admitted with
paracetamol toxicity weighing over
40kg
Version
If this version supersedes another clinical guideline please be
explicit about which guideline it replaces including version number.
Statement of the evidence base of the guideline – has the
guideline been peer reviewed by colleagues?
Evidence base: (1-6)
1
NICE Guidance, Royal College Guideline, SIGN
(please state which source).
2a
meta analysis of randomised controlled trials
2b
at least one randomised controlled trial
3a
at least one well-designed controlled study without
randomisation
3b
at least one other type of well-designed quasiexperimental study
4
well –designed non-experimental descriptive
studies (ie comparative / correlation and case
studies)
5
expert committee reports or opinions and / or
clinical experiences of respected authorities
6
recommended best practise based on the clinical
experience of the guideline developer
Consultation Process
Ratified by:
Date:
Target audience
Review Date: (to be applied by the Integrated Governance Team)
Excludes: Paediatric patients
2.0
Version 1.0
-Joint Formulary Committee. British
National Formulary [Ed]. [edition no.
70] London: British Medical
Association and Royal Pharmaceutical
Society of Great Britain; September
2015]. Accessed via medicines
complete 09/02/2016
-Parvolex Summary of product
characteristics [last updated –
14/11/2014] on Electronic Medicines
Compendium: (accessed on
[09/02/2016]) via
www.medicines.org.uk/
-Paracetamol Overdose. Toxbase.
[last updated 09/2014 (accessed on
09/02/2016) via www.toxbase.org
-The College of Emergency Medicine
Information 3rd September 2012
Dr Navin Bedi (ED Consultant)
ED Clinical Governance Group
NUH Medicines Management
Committee: Prescribing to be done on
pre-printed “Intravenous
Acetylcysteine for Paracetamol
Toxicity in Adults” prescription label
(MMC05/12b, Review date 02/19)
Drugs and Therapeutics Committee
February 2016
NUH Intranet
Emergency Department Staff
Admissions Ward Staff
February 2019
A review date of 5 years will be applied by the Trust. Directorates
can choose to apply a shorter review date, however this must be
managed through Directorate Governance processes.
This guideline has been registered with the trust. However, clinical guidelines are guidelines only.
The interpretation and application of clinical guidelines will remain the responsibility of the
individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using
guidelines after the review date.
TRUST WIDE INTRAVENOUS ACETYLCYSTEINE FOR
PARACETAMOL TOXICITY IN ADULTS GUIDELINE
USES AND MANAGEMENT

Paracetamol overdosage. To be used as recommended in the national guidelines.
Treatment is most effective if started within 8 hours following overdose.

Following a single acute overdose, taken over less than one hour, the need for treatment with
acetylcysteine is determined by plotting the measured plasma paracetamol concentration against
the time since ingestion commenced using a nomogram (see below).

Patients whose plasma-paracetamol concentrations are on or above the treatment line should be
treated with acetylcysteine by intravenous infusion. The single treatment line is applicable whether
or not patients have additional risk factors for liver toxicity.

Treatment should be given in all patients where there is doubt over the time of the ingestion and the
dose ingested is more than or equal to 150 mg/kg in any 24 hour period. Clinical judgement should
be used in determining the need for treatment if there is doubt over the time of the ingestion and the
dose ingested is between 75 and 150 mg/kg in any 24 hour period.

For patients who present 8-24 hours after taking a potentially toxic amount of paracetamol of more
than 150mg/kg, even if the plasma-paracetamol concentrations are not yet available.
If more than 24 hours have elapsed since ingestion or there is no IV access follow advice on
Toxbase, accessed via www.toxbase.org. Contact Emergency Department or Pharmacy
Department for Advice.
INITIAL BLOOD TESTS






Paracetamol level
INR
Plasma Creatinine
Venous pH or plasma bicarbonate
ALT
U&Es
Page 2 of 8
STAGGARED PARACETAMOL OVERDOSE (DOSES TAKEN OVER MORE THAN 1 HOUR)
These patients require careful assessment. Risk assessment is based on the history of staggered
dose and timing of paracetamol ingestion, the presence or absence of clinical features suggestive
of paracetamol toxicity, and the results of blood tests.





Patients with clinical features of hepatic injury such as jaundice or hepatic tenderness should be
treated urgently with acetylcysteine.
Serious toxicity may occur in patients ingesting more than 150 mg/kg in any 24-hour period.
Rarely, toxicity can occur with ingestions between 75 and 150 mg/kg within any 24-hour period in
some patients.
Doses less than 75 mg/kg within 24 hours are very unlikely to be toxic.
Ingestion of a licensed dose is not considered an overdose (e.g. in adults 4 g in a 24-hour period).
For patients who have taken a staggered overdose (i.e. over more than one hour), the Commission on
Human Medicines (CHM) has recommended that treatment with acetylcysteine should be given and that
individual risk factors should no longer be used in the assessment.
Clinically significant hepatotoxicity is unlikely if, 24 hours or longer after the last paracetamol ingestion, all
the following criteria are met:
 the paracetamol concentration is not detectable
 the INR is 1.3 or less
 ALT is less than two times the upper limit of normal
 the patient is asymptomatic.
The patient is not considered to be at risk of liver damage and does not need treatment with acetylcysteine.
If the patient also has a normal serum creatinine, they can be discharged with advice to return to hospital if
vomiting or abdominal pain occurs.
Clinicians should be aware that the dose or timing reported in overdose may be unreliable and if there is
any uncertainty the patient should be treated with acetylcysteine.
Page 3 of 8
DOSING INFORMATION
Dose 1
Dose 2
Dose 3
Acetylcysteine 150mg/kg in 200ml Glucose 5% over 1 hour
Acetylcysteine 50mg/kg in 500ml Glucose 5% over 4 hours
Acetylcysteine 100mg/kg in 1000ml Glucose 5% over 16 hours
See dosing table on page 6
Preferred infusion fluid is Glucose 5%, if this is not suitable then sodium chloride 0.9% may be used
For patients that weigh over 110kg the acetylcysteine dose should be based on a maximum of 110
kg.
For patients that weigh less than 40kg use paediatric dosage information accessed via the online
BNFC or refer to current PICU Acetylcysteine Pharmacopoeia monograph
Pregnant patients:
Toxic dose should be calculated using the patient’s pre-pregnancy weight and the antidote dose should be
calculated using the patient’s actual pregnant weight.
PRESENTATION
Acetylcysteine injection 2grams in 10ml (200mg/ml). Further dilute for infusion.
COMPATIBILITY
Glucose 5% is the preferred infusion fluid. If this cannot be used Sodium Chloride 0.9% can be used
instead.
Y SITE COMPATIBILITY
Nil known
COMMENTS
A change in the colour of the solution to light purple has sometimes been noted and is not thought to
indicate significant impairment of safety or efficacy.
MONITORING
Plasma potassium monitoring is recommended as hypokalaemia has been seen in patients with
paracetamol poisoning.
Page 4 of 8
ADVERSE EFFECTS
Anaphylactoid reactions
Anaphylactoid hypersensitivity reactions occur with acetylcysteine in up to 20% of patients, particularly with
the initial loading dose and usually occur between 15 and 60 minutes after starting the infusion and is
usually relieved by stopping the infusion.
Most anaphylactoid reactions can be managed by temporally suspending the acetylcysteine infusion,
administering appropriate supportive care e.g. an H1 antihistamine such as chlorphenamine 10 mg IV and
nebulised salbutamol if bronchospasm is significant and then restarting treatment at a lower infusion rate.
Once an anaphylactoid reaction is under control, the infusion can normally be restarted at an infusion rate
of 50 mg/kg over 4 hours, followed by the final 16 hour infusion (100 mg/kg over 16 hours).
A previous anaphylactoid reaction to acetylcysteine is NOT an absolute contraindication for a further
treatment course. For patients who have previously had a severe reaction to acetylcysteine treatment,
consider giving the first bag more slowly than normal, e.g. over 2 hours. Acetylcysteine is more likely to
cause adverse effects if paracetamol concentrations are low or absent. They are more likely to occur in
women, asthmatics and in patients with a family history of allergy.
If there has been a previous allergic reaction to acetylcysteine prophylactic treatment with H1 and H2
antihistamines should be considered e.g.

Chlorphenamine 10 mg IV and

Ranitidine 50 mg diluted to 20 mL and given intravenously over at least 2 minutes
Pretreatment with a salbutamol nebule may be considered for patients with a history of bronchospasm
following acetylcysteine treatment, occasionally corticosteroids may be required. The patient should be
carefully observed during this period for signs of an anaphylactoid reaction. Nausea, vomiting, flushing, skin
rash, pruritus and urticaria are the most common features, but more serious anaphylactoid reactions have
been reported where the patient develops angioedema, bronchospasm, respiratory distress, tachycardia
and hypotension. In very rare cases these reactions have been fatal. There is some evidence that patients
with a history of atopy and asthma may be at increased risk of developing an anaphylactoid reaction.
Coagulation
Changes in haemostatic parameters have been observed in association with acetylcysteine treatment,
some leading to decreased prothrombin time, but most leading to a small increase in prothrombin time and
INR. An isolated increase in prothombin time up to 1.3 at the end of a 21 hour course of acetylcysteine
without an elevated transaminase activity do not require further monitoring or treatment with acetylcysteine.
Fluid and electrolytes
Use with caution in children, patients requiring fluid restriction or those who weigh less than <40 kg
because of the risk of fluid overload which may result in hyponatraemia and seizures which may be life
threatening.
Each 10ml (2g) of acetylcysteine injection contains 322.6mg sodium. To be taken into consideration with
patients on a controlled sodium diet.
Page 5 of 8
MANAGEMENT AFTER THE 21 HOUR INFUSION:
Re-check and review:
 Paracetamol level
 INR
 Plasma Creatinine
 Venous pH or plasma bicarbonate
 ALT
 U&Es
If all blood results are normal (INR is 1.3 or less, ALT is less than two times the upper limit of normal, and
ALT is not more than double the admission measurement), the patient can be considered medically fit for
discharge, although with advice to return to hospital if vomiting or abdominal pain occurs. Consider the
need for a DPM referral.
If there is a delay in the review and interpretation of blood results then the infusion should be continued
until such a review occurs and a decision is made that the infusions are no longer needed and can be
stopped.
If blood results are abnormal:



the ALT has more than doubled since the admission measurement, OR
the ALT is two times the upper limit of normal or more, OR
the INR is greater than 1.3 (in the absence of another cause, e.g. warfarin)
Continue acetylcysteine 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 816 hours.
An isolated smaller (up to two times the upper limit of normal) rise in ALT in the presence of an INR of 1.3
or less does not require further treatment. The patient can be discharged with advice to return to hospital if
vomiting or abdominal pain occurs.
ADDITIONAL INFORMATION:
Methionine
Discontinued in the UK. Formerly used for treatment of paracetamol poisoning. Superseded by
acetylcysteine (NAC, Parvolex®).
Page 6 of 8
METHOD OF ADMINISTRATION
A total dose is divided into 3 consecutive intravenous infusions over a total of 21 hours. Doses should be
administered sequentially with no break between the infusions.
Acetylcysteine Dosing Table
Regimen
Infusion
Fluid
Duration of
infusion
Drug dose
Patient
Weight
Kg
40-49
50-59
60-69
70-79
80-89
90-99
100-109
> 110 Max
dose
First Infusion
200 mls 5% Glucose or
Sodium Chloride 0.9%
1 hour
Second Infusion
500 mls 5% Glucose or
Sodium Chloride 0.9%
4 hours
Third Infusion
1000 mls 5% Glucose or
Sodium Chloride 0.9%
16 hours
150mg/kg
Acetylcysteine
Dose (gram)
Infusion
and
Rate
(Ampoule
volume*)
ml/h
50mg/kg
Acetylcysteine
Dose (gram)
Infusion
And
Rate
(Ampoule
volume*)
ml/h
100mg/kg
Acetylcysteine
Dose (gram)
Infusion
and
Rate
(Ampoule
volume*)
ml/h
6.8g
(34ml)
8.4g
(42ml)
9.8g
(49ml)
11.4g
(57ml)
12.8g
(64ml)
14.4g
(72ml)
15.8g
(79ml)
16.6g
(83ml)
234
242
249
257
264
272
279
283
2.4g
(12ml)
2.8g
(14ml)
3.4g
(17ml)
3.8g
(19ml)
4.4g
(22ml)
4.8g
(24ml)
5.4g
(27ml)
5.6g
(28ml)
128
129
129
130
131
131
132
132
4.6g
(23ml)
5.6g
(28ml)
6.6g
(33ml)
7.6g
(38ml)
8.6g
(43ml)
9.6g
(48 ml)
10.6g
(53ml)
11.0g
(55ml)
64
64
65
65
65
66
66
66
Dose calculations are based on the weight in the middle of each band.
Ampoule volume has been rounded up to the nearest whole number
For patients that weigh over 110kg the acetylcysteine dose should be based on a maximum of 110
kg.
For patients that weigh less than 40kg use paediatric dosage information accessed via the online
BNFC or refer to current PICU Acetylcysteine Pharmacopoeia monograph
* Acetylcysteine injection 2grams in 10ml (200mg/ml)
Page 7 of 8
HOW TO PRESCRIBE
Complete and stick a pre-printed Acetylcysteine prescription label (see below) to the Infusion Therapy
prescription on the back of the Trust drug chart, ensuring that it is correctly positioned to allow completion
of the administration and signing section of the drug chart.
Labels are stocked in ED, D57, B3 at QMC and SRU at City Campus and available through pharmacy
stores.
Intravenous Acetylcysteine for Paracetamol Toxicity in Adult Patients Weight
(kg) …………
Date
Route
Infusion Fluid
Volume
(ml)
IV
Glucose 5%
200ml
Additives
Dose (Gram)
(or use dose
banding table)
Rate or
Duration
Prescriber’s Signature
(Print name and
Profession and Bleep)
Acetylcysteine
1 hour
150mg/kg
IV
Glucose 5%
500ml
Acetylcysteine
4 hours
50mg/kg
IV
Glucose 5%
1000ml
Acetylcysteine
16 hours
100mg/kg
For patients that weigh over 110kg the acetylcysteine dose should be based on a maximum of
110kg
For patients that weight less than 40kg use paediatric dosage table
Preferred infusion fluid is Glucose 5%, if this is not suitable then sodium chloride 0.9% may be used
Page 8 of 8