Paracetamol poisoning

Paracetamol poisoning can cause gastroenteritis within a few hours and liver damage within 1-3 days after ingestion. The severity of damage to the liver after a single acute overdose can be predicted by the concentration of paracetamol in the blood plasma.

Treatment with acetylcysteine prevents or minimizes hepatotoxicity of paracetamol.

[1], [2],

Pathogenesis

Paracetamol is contained in more than 100 over-the-counter drugs, including medicines for children (capsules, tablets and syrups), as well as drugs used for cough and cold. Many prescription drugs also contain paracetamol. In this regard, paracetamol overdose is common. The main toxic metabolite of paracetamol, N-acetyl-b-benzoquinone imine, is produced by the liver cytochrome P450 enzyme system; neutralized in the liver with glutathione. Acute overdose depletes glutathione in the liver. As a result, N-acetyl-b-benzoquinoneamine accumulates, causing hepatocyte necrosis, possibly causing damage to other organs (kidney, pancreas). Theoretically, alcoholic liver disease and reduced nutrition can increase the risk of damage, since the state of the hepatocyte enzyme system causes an increased formation of N-acetyl-b-benzoquinone-imine, and as a result of depletion (which is typical for alcoholics) leads to a decrease in glutathione reserves. However, it is unclear whether the risk actually increases. Alcohol intake may have a protective effect, since the hepatic enzymes of the P450 system preferably metabolize ethanol and, as a result, cannot produce toxic N-acetyl-b-benzoquinoneimine.

For poisoning, an acute overdose is needed totaling> 150 mg / kg body weight (about 7 g for adults) during the day.

Chronic overuse or repeated overdose lead to liver damage in rare cases. Chronic overdose is usually caused by taking an unreasonably high amount of a drug to treat pain, rather than deliberate poisoning.

[3], [4], [5], [6], [7], [8], [9]

Symptoms of the paracetamol poisoning

Mild poisoning can be asymptomatic, or the symptoms are minimally pronounced within 48 hours from the moment of taking the drug.

[10], [11], [12], [13]

Acute single overdose with paracetamol

The clinical symptoms that go through 4 stages include anorexia, vomiting, nausea, pain in the right hypochondrium. The activity of aspartate aminotransferase (ACT) and alanylaminotransferase (ALT) may increase, and in severe poisoning, total bilirubin and MHO may occur. Increased ACT activity> 1000 U / L is more likely to result from paracetamol poisoning than with chronic hepatitis or alcoholic liver disease. At the same time, renal failure and pancreatitis are possible, sometimes without liver failure. After 5 days, the liver damage either regresses or progresses to multiple organ failure, which is often fatal.

An overdose of paracetamol should be considered in all patients with non-random use of the drug, which can be a suicidal attempt, since this is characterized by an overdose. In addition, in the early stages, the symptoms of overdose are minimal, it is potentially fatal, but treatable, and patients with impaired consciousness or after suicide may not report it.

The probability and severity of liver damage can be predicted by the amount of the drug taken, or more precisely by its concentration in the blood. If you know the time of taking the drug, to predict the severity of liver damage, you can use the Ramak-Matthew nomogram? If the time of taking the drug is unknown, it is impossible to apply a nomogram. With a single acute overdose of traditional or fast-acting form (absorbed 7-8 minutes faster) of paracetamol, its concentration is measured after 4 hours from the moment of administration and the values are plotted on the nomogram. If the concentration is 150 µg / ml (990 mmol / l) and there are no symptoms of intoxication, the risk of liver damage is very low. A higher concentration indicates the possibility of liver failure. In case of overdose of prolonged paracetamol (which has 2 concentration peaks with an interval of 4 hours), its concentration is measured 4 hours after administration and again after 4 hours. Treatment is indicated if one of the indicators exceeds the parameters of the Rumack-Matthew line.

[14], [15], [16], [17], [18],

Chronic paracetamol overdose

Symptoms may be absent or resemble those with acute overdose. The Ramak-Matthew nomogram is not used, but the probability of clinically significant hepatic failure can be estimated based on the activity of aminotransferases and the concentration of paracetamol in the blood. With normal ACT and ALT (<50 U / L) and paracetamol concentration <10 μg / ml, liver damage is unlikely. If the activity of aminotransferases is within the normal range, but the concentration of paracetamol is> 10 μg / ml and there is a possibility of liver damage, it is necessary to re-examine the activity of ACT and ALT during the day. If the re-measurement of enzyme activity is not increased - the risk of liver failure is small, with increased activity, we can assume the development of liver damage. Liver damage should also be assumed in the case of initially high activity of aminotransferases, regardless of the concentration of paracetamol in the blood.

[19], [20], [21], [22], [23],

Stages

Stage	Time from reception	Description
I	0-24h	Anorexia, nausea and vomiting
II	24-72 h	Pain in the right hypochondrium (characteristic); ALT, ACT, and in severe poisoning, total bilirubin and MHO can be increased
III	72-96 h	Vomiting and signs of liver failure; ALT, ACT, total bilirubin and MHO peak values; in some cases kidney failure and pancreatitis develop
IV	> 5 days	Regress of liver damage or its progression to multiple organ failure (sometimes fatal)

[24]

Treatment of the paracetamol poisoning

If it is assumed that paracetamol is present in the gastrointestinal tract, activated carbon is prescribed. Acetylcysteine is an antidote for paracetamol poisoning. It is a precursor of glutathione, which reduces the toxicity of paracetamol due to an increase in glutathione in the liver and, possibly, due to other mechanisms.

In acute poisoning, acetylcysteine is prescribed if the probability of liver damage is based on the dose of paracetamol or its concentration in the blood plasma. The most effective drug in the first 8 hours after poisoning.

In chronic poisoning, acetylcysteine is prescribed for the first 24 hours, if liver damage is likely (ALT and ACT are not elevated, the concentration of paracetamol is increased slightly). If at repeated (after 24 h) the study of ALT and ACT are not increased, the introduction of acetylcysteine is stopped. In the event of an increase in ACT and ALT, daily monitoring of the enzyme and continued acetylcysteine therapy is necessary until these parameters normalize. If liver damage is likely (especially with high activity of transaminamine upon admission), a full course of acetylcysteine therapy is performed.

Acetylcysteine is equally effective when administered intravenously and inside. Intravenous drug is administered in the form of a continuous infusion. A loading dose of 150 mg / kg per 200 ml of 5% glucose solution or 0.9% sodium chloride solution is administered over 15 minutes; then a maintenance dose of 50 mg / kg in 500 ml of 5% glucose solution or 0.9% sodium chloride solution is administered over 4 hours; then 100 mg / kg in 1000 ml of 5% glucose solution or 0.9% sodium chloride solution is administered over 16 hours. When treating children, dose adjustment is necessary to reduce the total fluid intake volume; recommended consultation with the Center for Control of Poisoning.

The loading dose of acetylcysteine when administered is 140 mg / kg, then another 17 additional doses of 70 mg / kg are prescribed every 4 hours. Because of the unpleasant taste, the drug is prescribed at a dilution of 1: 4 with a carbonated drink or juice, but still may cause vomiting. When vomiting, you can assign antiemetics; If vomiting occurs within the first hour after taking an antiemetic, it is taken again.

Treatment of liver failure supportive. Patients with fulminate liver failure may require a liver transplant.

Forecast

With appropriate treatment, mortality is low. By 24-48 hours, bad predictors are:

• pH <7.3 after adequate infusion therapy;
• INR> 3;
• creatinine> 2.6;
• hepatic encephalopathy stage III (confusion and drowsiness, semi-conscious state) or stage IV (stupor and coma);
• glipse and thrombocytopenia.

These parameters are examined after 24 and 48 hours from the moment of poisoning. Acute poisoning with paracetamol does not lead to the development of liver cirrhosis.

[25], [26], [27],