Acetaminophen Poisoning

Acetaminophen is the most widely used antipyretic and

analgesic. It is a combination agent in approximately

125 medications that has been deemed safe and

effective when used within recommended dosage. Its

therapeutic safety in children has been directly related

to absence of significant cumulative kinetics. In USA,

203,930 cases of actaminophen over ingestion were

reported to US poison centers between 1998 and 1999,

making it the leading pharmacologic agent associated

with toxicity.1 It is freely available in the market and

its use is widely known to general public. Careless

approach of family members towards its use and

storage results in high incidence of accidental overdose

in children particularly below the age of 6 years, less

common but potentially more devastating is the suicide

attempt as manipulative episode in the adolescent.

Experience with acetaminophen overdosages further

indicates a considerable difference between the child

under age 6 years and adolescent.2 Following ingestion

metabolized in liver with less than 2% being excreted

unchanged in urine.4

In children, between 9 to 12 years of age, acetaminophen

is primarily metabolized in the liver to the sulfate

or glucuronide conjugates which are metabolically inert.

The remaining 2 to 4% is metabolized through

cytochrome p-450 mixed functions oxidase system

which conjugates it with glutathione to produce

mercaptopuric acid, a non-toxic product. The lower

incidence of toxicity in young children may be related

to lesser metabolism via p-450.5

With acetaminophen overdose, when hepatic stores

of glutathione are depleted to less than 70% of normal,

the highly reactive intermediate toxic metabolites bind

with hepatic macromolecules and cause hepatic

necrosis.6 Hepatic enzyme induction by barbiturates,

narcotics, hydantoin and histamines may increase the

formation of reactive metabolites, predisposing the

patient to hepatic damage even if a minor overdose of

acetaminophen is ingested.7 Co-ingestion of ethanol and

acetaminophen is cytoprotective in both adults and

children, probably as a result of competition at P-450

site but ethanol is not recommended as therapy.8

Chronic acetaminophen poisoning is rare as

approximately 98% of the drug is metabolized by liver,

children receiving therapeutic doses of acetaminophen

over a long time should have no difficulty in managing

the small load of toxic metabolites with constantly

regenerating glutathione stores in liver. Therapeutic

accumulation to plasma levels of 40 μg/dl which is

still under that required for hepatotoxicity may occur

if the highest recommended dose of 15 mg/kg is given

every 4 hours for extended period, child abuse or

intentional overdose must be considered in children

who develop high plasma levels at therapeutic

overdose.9

Clinical Features

Children with overdose of acetaminophen usually

present with features of hepatic cell damage, renal

tubular necrosis and hypoglycemic coma. They pass

through following four stages of toxicity if left

untreated.10

Stage I: This stage lasts for first 24 hours after

ingestion. Average time of onset of symptoms

is 6 hours after ingestion and children usually

become symptomatic by 14 hours. In this

stage child usually presents with anorexia,

nausea, vomiting, malaise, pallor and

diaphoresis, children less than 6 years of age

rarely show diaphoresis but present with

early vomiting. Laboratory investigations

such as ALT, AST, serum bilirubin and

prothrombin time are normal in this stage.

Stage II: This stage lasts for next 24 hours after

stage I. It is characterized by resolution of

symptoms of stage I with upper quadrant

abdominal pain and tenderness. Mild

hepatomegaly and jaundice may also be

present. Laboratory investigations show

elevated serum bilirubin, AST, ALT and

prothrombin time. Some children may

develop oliguria.

Stage III: This stage is seen 48 hours to 96 hours after

ingestion. Maximum liver functions abnormalities

are seen during this period.

Hepatotoxicity due to acetaminophen is

characterized by elevated transaminases,

increased serum bilirubin and prolonged

prothrombin time.

Plasma AST level in excess of 1000 IU/L,

prolongation of prothrombin time and serum

bilirubin more than 4 mg/dL on 3rd to fifth

day after ingestion are indicators of severe

toxicity.11 Acute renal failure may also occur

in some patients. Anorexia, nausea, vomiting

and malaise may reappear during this stage.

Less than 1% of patients in stage III develops

fulminant hepatotoxicity and eventually dies

of hepatic failure, if left untreated. Liver

biopsy in this stage reveals centrilobular

necrosis of hepatocytes with sparing of

periportal area.

Stage IV: This is the stage of resolution and extends

from 4 days to two weeks. It is characte-rized

by resolution of hepatic dysfunction although

AST may remain elevated for few more days.

On follow up of patients who had hepatotoxicity,

usually revealed no sequelae either

clinically or on liver biopsy, three months to

one year later.

Diagnosis

1. History of ingestion

2. Clinical features

3. Laboratory investigations

a. Plasma level of acetaminophen to assess the

severity of hepatotoxicity: Serum concentrations

greater than 200, 100 and 50 μg/ml at 4, 8 and 12

hours after ingestion respectively or any

concentration above the values depicted on the

Rumack Mathew normogram indicates a potential

risk of hepatotoxicity.2

b. Plasma AST level greater than 1000 IU/L

 c. Bilirubin more than 4 mg/dL

d. Prolonged prothrombin time.

Management

1. Assessment: In children with acetaminophen

overdose, efforts should be made to determine the

amount of drugs or other co-ingestants which may

also have been involved. Acetaminophen alone will

not produce any alteration in the sensorium in first

24 hours and usually will not produce such an

alteration unless patient develops hepatic

encephalopathy. Thus, if a patient comes with a

significant change in sensorium, some other agents

should be considered in addition to or instead of

acetaminophen care of airways, breathing and

circulation should be done properly. A sample of

blood should be drawn and sent for laboratory

investigations including serum acetaminophen level.

2. General measures: When a child presents with a

history acetaminophen overdose within 4 hours,

gastrointestinal decontamination should be done.

Emesis should be induced with syrup of ipecac to

get rid of remaining acetaminophen. Gastric lavage

must be done with normal saline. Activated charcoal

is effective in adsorbing acetaminophen. In physiological

pH range, adsorption is rapid and pH

independent.12 The dose of activated charcoal is

10 times the ingested dose of acetaminophen.

Activated charcoal appears to reduce the number of

patients who achieve toxic acetaminophen concentrations

and thus may reduce the need for treatment

and hospital stay.13 For maximal effect, activated

charcoal should be administered within 30 minutes

of ingestion. However, in vitro experiments, activated

charcoal effectively adsorbs both methionine and

N-acetylcysteine, concurrent administration of

both would markedly diminish their antidotal

effectiveness.14

Specific Measures

N-acetylcysteine is the specific antidote and drug of

choice for prevention of hepatotoxicity. Other drugs like

methionine, cysteamine are available but are not popular

due to their side effect. Oral or intravenous N-acetyl

cysteine mitigates acetaminophen induced hepatorenal

damage as demonstrated by prevention of elevation of

serum transamiases, bilirubin and prolongation of

prothrombin time, if given within 10 hours but becomes

less effective thereafter. In vivo, N-acetyl cysteine forms

L-cysteine, cystine, L-methionine, glutathione and mixed

disulfides; L-methionine also forms cysteine thus giving

rise to glutathione and other products.15 The beneficial

effects of N-acetyl cysteine include improvement of liver

blood flow, glutathione replenishment, modification of

cytokine production and free radical oxygen

scavenging.16

The oral dosage schedule of N-acetylcysteine is

140 mg/kg of body weight as loading dose followed by

subsequent doses of 70 mg/kg body weight at 4 hourly

intervals for an additional 17 doses.17 If the patient

vomits within an hour of administration of dose, it

should be repeated. If there is persistent vomiting, a

nasogastric tube should be inserted, preferably into the

duodenum. The optimal route and duration of

administration of N-acetylcysteine are controversial. On

the basis of selected Post-hoc analysis, oral N-acetyl

cysteine was found superior to intravenous route in

presentations later than 15 hours. However, the

differences claimed between oral and intravenous Nacetylcysteine

regimes are probably artifactual and relate

to inappropriate subgroup analysis. A shorter hospital

stay, patient and doctor convenience and the concerns

over the reduction in bioavailability of oral Nacetylcysteine

by charcoal and vomiting make

intravenous N-acetylcysteine preferable for most patients

with acetaminophen poisoning (Table 49.4.1).18 The

administration of activated charcoal before oral N-acetyl

cysteine in acetaminophen overdose does not reduce the

efficacy of N-acetylcysteine and may provide additional

hepatoprotective benefit. However, some workers have

suggested increment of loading dose by 40% or from

140 mg/kg to 235 mg/kg body weight.19

As unpleasant odor and frequent vomiting is

associated with its use, the concentration of N-acetylcysteine

should be diluted to a final concentration of

5%(w/v) and to mask the unpleasant flavor, citrus fruit

juices or carbonated beverages should be added with

intravenous preparations loading dose should be given

with 200 ml of 5% dextrose over 15 minutes followed

by subsequent doses in 500 ml dextrose over 4-8 hours.

Table 49.4.1: Biochemical and hematological

abnormalities in paracetamol poisoning

Biochemical ↑ ALT/AST

↑ Bilirubin

↓ Blood glucose

↓ Lactase

↑ Amylase

↑ Creatinine

↓ Phosphate

Hematological Thrombocytopenia

↑ Prothrombin time

↓ Clotting factors II, V, VII

 

Management of Specific Toxicological Emergencies 47477777

Nausea, vomiting and diarrhea may also occur as

results of oral N-acetylcysteine administration.

Anaphylactoid reactions including angioedema,

bronchospasm, flushing, hypotension, hypokalemia,

nausea/vomiting, rashes, tachycardia and respiratory

distress may occur 15-60 minutes after N-acetylcysteine

infusion in up to 10% of patients. A reduction in the

loading dose of N-acetylcysteine may reduce the risk

of adverse reactions while maintaining efficacy.15 Oral

therapy with N-acetylcysteine or methionine for

acetaminophen poisoning is contraindicated in presence

of coma or vomiting or if activated charcoal has been

given by mouth. Hemodynamic and oxygen delivery

and utilization parameters must be monitored carefully

during delayed N-acetylcysteine treatment of patients

with fulminate hepatic failure, as unwanted

vasodilatation may be deleterious to the maintenance

of mean arterial blood pressure.16

The administration of N-acetylcysteine for longer

period might provide enhanced protection for patients

in whom acetaminophen absorption or elimination is

delayed. N-acetylcysteine may also have a role in

treatment of toxicity from carbon tetrachloride, chloroform,

1, 2-dichloropropane and other compounds.15

Methionine acts by replenishing cellular glutathione

stores or more probably through generation of cysteine

and/or glutathione. It acts also as a source of sulfate

and so unsaturates sulfate conjugation. Methionine is

more effective when given orally than IV. The initial

dose is 2.5 gm then 2.5 gm 4 hourly to a total of 10 gm

over 12 hours.14

During the course of treatment, laboratory investigations

should be repeated. If the liver function tests

begin to become abnormal, proper measures should be

taken. Once hepatic failure occurs, use of N-acetylcysteine

is contraindicated15 and patient should be

managed along conventional line with lactulose, vit-K,

20% mannitol and appropriate IV fluids. Renal function

should be evaluated periodically and necessary

measures should be taken, if deterioration occurs.

Forced alkaline diuresis is of no therapeutic value.

Hemodialysis or charcoal hemoperfusion enhances

elimination of acetaminophen but not the toxic

metabolites.

Prognosis

The poor prognostic factors in established paracetamol

induced hepatic failure are pH below 7.3, serum

creatinine above 300 μmol/L and prothrombin time

above 100 seconds in grade III to IV encephalopathy.

However, factor VIII to factor V ratio above 30 is the

best poor prognostic indicator.16

REFERENCES

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3. Peterson RG, Rumack BH. Age as variable in acetaminophen

overdose. Arch Intern Med 1981; 141:390-3.

4. Rumack BH. Acetaminophen overdose in young

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5. Lich Lai MW, Sarnaik AP, Newton JE. Metabolism and

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