Paracetamol poisoning

The third phase follows at 3 to 5 days, and is marked by complications of massive liver necrosis leading to fulminant liver failure with complications of coagulation defects, low blood sugar, kidney failure, hepatic encephalopathy, brain swelling, sepsis, multiple organ failure, and death.^[10] If the third phase is survived, the liver necrosis runs its course, and liver and kidney function typically return to normal in a few weeks.^[16] The severity of paracetamol toxicity varies depending on the dose and whether appropriate treatment is received.

Cause

The toxic dose of paracetamol is highly variable. In general the recommended maximum daily dose for healthy adults is 4 grams.^[17][18] Higher doses lead to increasing risk of toxicity. In adults, single doses above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing toxicity.^[19][20] Toxicity can also occur when multiple smaller doses within 24 hours exceed these levels.^[20] Following a dose of 1 gram of paracetamol four times a day for two weeks, patients can expect an increase in alanine transaminase in their liver to typically about three times the normal value.^[21] It is unlikely that this dose would lead to liver failure.^[22] Studies have shown significant hepatotoxicity is uncommon in patients who have taken greater than normal doses over 3 to 4 days.^[23] In adults, a dose of 6 grams a day over the preceding 48 hours could potentially lead to toxicity,^[20] while in children acute doses above 200 mg/kg could potentially cause toxicity.^[24] Acute paracetamol overdose in children rarely causes illness or death, and it is very uncommon for children to have levels that require treatment, with chronic larger-than-normal doses being the major cause of toxicity in children.^[20]

Intentional overdosing (self-poisoning, with suicidal intent) is frequently implicated in paracetamol toxicity.^[25] In a 2006 review, paracetamol was the most frequently ingested compound in intentional overdosing.^[26]

In rare individuals, paracetamol toxicity can result from normal use.

Fasting is a risk factor, possibly because of depletion of liver glutathione reserves.^[20] The concomitant use of the CYP2E1 inducer isoniazid increases the risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear.^[32][33] Concomitant use of other drugs that induce CYP enzymes, such as antiepileptics including carbamazepine, phenytoin, and barbiturates, have also been reported as risk factors.^[34]

Pathophysiology

When taken in normal therapeutic doses, paracetamol has been shown to be safe.

In cases of paracetamol overdose, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become depleted, as the demand for glutathione is higher than its regeneration.[39] NAPQI therefore remains in its toxic form in the liver and reacts with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute liver necrosis.^[35][40] In animal studies, the liver's stores of glutathione must be depleted to less than 70% of normal levels before liver toxicity occurs.^[36]

Diagnosis

A person's history of taking paracetamol is somewhat accurate for the diagnosis.^[41] The most effective way to diagnose poisoning is by obtaining a blood paracetamol level. A drug nomogram developed in 1975, called the Rumack–Matthew nomogram, estimates the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion.^[10] To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the nomogram. Use of a timed serum paracetamol level plotted on the nomogram appears to be the best marker indicating the potential for liver injury.^[20] A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Therefore, a serum level taken before 4 hours is not recommended.^[19]

Clinical or biochemical evidence of liver toxicity may develop in one to four days, although, in severe cases, it may be evident in 12 hours.^[42] Right-upper-quadrant tenderness may be present and can aid in diagnosis. Laboratory studies may show evidence of liver necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times, particularly an elevated prothrombin time.^[43] After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed.^[42] In some cases, the AST and ALT levels can exceed 10,000 IU/L.^[44]

Detection in body fluids

Paracetamol may be quantified in blood, plasma, or urine as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths. The concentration in serum after a typical dose of paracetamol usually peaks below 30 mg/L, which equals 200 μmol/L.^[45] Levels of 30–300 mg/L (200–2000 μmol/L) are often observed in overdose patients. Postmortem blood levels have ranged from 50 to 400 mg/L in persons dying due to acute overdosage. Automated colorimetric techniques, gas chromatography and liquid chromatography are currently in use for the laboratory analysis of the drug in physiological specimens.^[46][47]

Prevention

Limitation of availability

Limiting the availability of paracetamol tablets has been attempted in some countries. In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 x 500 mg tablets in pharmacies, and 16 x 500 mg tablets in non-pharmacy outlets. Pharmacists may provide up to 100 tablets for those with chronic conditions at the pharmacist's discretion.^[48][49] In Ireland, the limits are 24 and 12 tablets, respectively.^[50] Subsequent study suggests that the reduced availability in large numbers had a significant effect in reducing poisoning deaths from paracetamol overdose.^[51]

One suggested method of prevention is to make paracetamol a prescription-only medicine, or to remove it entirely from the market. However, overdose is a relatively minor problem; for example, 0.08% of the UK population (over 50 thousand people) present with paracetamol overdose each year. In contrast, paracetamol is a safe and effective medication that is taken without complications by millions of people.

There have been no studies so far on the effectiveness of paracetamol when given in combination with its most commonly used antidote, acetylcysteine.[55]

Calcitriol, the active metabolite of vitamin D₃, appears to be a catalyst for glutathione production.^[56] Calcitriol was found to increase glutathione levels in rat astrocyte primary cultures on average by 42%, increasing glutathione protein concentrations from 29 nmol/mg to 41 nmol/mg, 24 and 48 hours after administration; it continued to have an influence on glutathione levels 96 hours after administration.^[57] It has been proposed that co-administration of calcitriol, via injection, may improve treatment outcomes.

Paracetamol replacements

Paracetamol ester prodrug containing L-pyroglutamic acid (PGA), a biosynthetic precursor of glutathione, has been synthesized to reduce paracetamol hepatotoxicity and improve bioavailability. The toxicological studies of different paracetamol esters show that L-5-oxo-pyrrolidine-2-paracetamol carboxylate reduces toxicity after administration of an overdose of paracetamol to mice. The liver glutathione values in mice induced by intraperitoneal injection of the ester are superimposable with the GSH levels recorded in untreated mice control group. The mice group treated with an equivalent dose of paracetamol showed a significant decrease of glutathione of 35% (p<0.01 vs untreated control group). The oral LD50 was found to be greater than 2000 mg kg-1, whereas the intraperitoneal LD50 was 1900 mg kg-1. These results taken together with the good hydrolysis and bioavailability data show that this ester is a potential candidate as a prodrug of paracetamol.^[58]

Treatment

Gastrointestinal decontamination

In adults, the initial treatment for paracetamol overdose is gastrointestinal decontamination. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe.

Inducing vomiting with syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated charcoal and oral acetylcysteine.^[19] Liver injury is extremely rare after acute accidental ingestion in children under 6 years of age. Children with accidental exposures do not require gastrointestinal decontamination with either gastric lavage, activated charcoal, or syrup of ipecac.^[20]

Acetylcysteine

If the person presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity and guarantees survival.[20] If acetylcysteine is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute liver necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion.^[71] If the person presents more than eight hours after the paracetamol overdose, then activated charcoal is not useful, and acetylcysteine is started immediately. In earlier presentations, charcoal can be given when the patient arrives and acetylcysteine is initiated while waiting for the paracetamol level results to return from the laboratory.^[20]

In United States practice,

Intravenous acetylcysteine is given as a continuous infusion over 20 hours for a total dose 300 mg/kg. Recommended administration involves infusion of a 150 mg/kg loading dose over 15 to 60 minutes, followed by a 50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol.[20] Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and allowing administration of activated charcoal to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine.^{[77][needs update]} Intravenous dosing varies with weight, specifically in children. For patients less than 20 kg, the loading dose is 150 mg/kg in 3 mL/kg diluent, administered over 60 minutes; the second dose is 50 mg/kg in 7 mL/kg diluent over 4 hours; and the third and final dose is 100 mg/kg in 14 mL/kg diluent over 16 hours.^[76] Because of the risk of adverse events, electrolyte derangements and fluid shifts associated with larger doses of acetylcysteine dose capping regimens have been suggested. To date no increased risk of hepatic injury or failure has been noted with this dose capping strategy.^[78]

The most common adverse effect to acetylcysteine treatment is an anaphylactoid reaction, usually manifested by rash, wheeze, or mild hypotension. Adverse reactions are more common in people treated with IV acetylcysteine, occurring in up to 20% of patients.^[79][80] Anaphylactoid reactions are more likely to occur with the first infusion (the loading dose).^[79] Rarely, severe life-threatening reactions may occur in predisposed individuals, such as patients with asthma or atopic dermatitis, and may be characterized by respiratory distress, facial swelling, and even death.^[79][81][82]

If an anaphylactoid reaction occurs the acetylcysteine is temporarily halted or slowed and antihistamines and other supportive care is administered.^[79][83][84] For example, a nebulised beta-agonist like salbutamol may be indicated in the event of significant bronchospasm (or prophylactically in patients with a history of bronchospasm secondary to acetylcysteine). It is also important to closely monitor fluids and electrolytes.^[79]

Liver transplant

In people who develop acute liver failure or who are otherwise expected to die from liver failure, the mainstay of management is liver transplantation.^[52] Liver transplants are performed in specialist centers. The most commonly used criteria for liver transplant were developed by physicians at King's College Hospital in London. Patients are recommended for transplant if they have an arterial blood pH less than 7.3 after fluid resuscitation or if a patient has Grade III or IV encephalopathy, a prothrombin time greater than 100 seconds, and a serum creatinine greater than 300 mmol/L In a 24-hour period.^[85] Other forms of liver support have been used including partial liver transplants. These techniques have the advantage of supporting the patient while their own liver regenerates. Once liver function returns immunosuppressive drugs are commenced and they have to take immunosuppressive medication for the rest of their lives.^[86][87]

Prognosis

The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Acidosis is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH less than 7.30. Other indicators of poor prognosis include chronic kidney disease (stage 3 or worse), hepatic encephalopathy, a markedly elevated prothrombin time, or an elevated blood lactic acid level (lactic acidosis).^[85][88] One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).^[89] Patients with a poor prognosis are usually identified for likely liver transplantation.^[85] Patients that do not die are expected to fully recover and have a normal life expectancy and quality of life.^[90]

Epidemiology

Many over-the-counter and prescription-only medications contain paracetamol. Because of its wide availability paired with comparably high toxicity, (compared to ibuprofen and aspirin) there is a much higher potential for overdose.^[91] Paracetamol toxicity is one of the most common causes of poisoning worldwide.^[25] In the United States, the United Kingdom, Australia, and New Zealand, paracetamol is the most common cause of drug overdoses.^[20][92][93] Additionally, in both the United States and the United Kingdom it is the most common cause of acute liver failure.^[94][9]

In England and Wales an estimated 41,200 cases of paracetamol poisoning occurred in 1989 to 1990, with a mortality of 0.40%. It is estimated that 150 to 200 deaths and 15 to 20 liver transplants occur as a result of poisoning each year in England and Wales.^[80] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year.^[95] A study of cases of acute liver failure between November 2000 and October 2004 by the Centers for Disease Control and Prevention in the US found that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.^[96]

References