Paracetamol

Paracetamol is by far the commonest paediatric poisoning presentation to the Emergency Department (ED), but the large majority will have no toxic effects. Absorption from the gastrointestinal (GI) tract is rapid, particularly with the liquid formulation (approx. 30 minutes). Most of the paracetamol is conjugated by the hepatic pathways of sulfation and glucuronidation to inactive metabolites, which are excreted in the urine. Children under the age of 9–12 years have a more active sulfation pathway. Less than 5% is excreted unchanged by the kidney and 5–15% is oxidised by the hepatic cytochrome P450 enzyme system to form a highly reactive intermediate metabolite – NAPQI (N-acetyl-p-benzoquinone imine), which binds to hepatocytes and leads to oxidative stress and cell death. With therapeutic dosing, NAPQI is metabolized to a non-toxic metabolite with glutathione as a sulfhydryl donor. In overdose, when glutathione reserves are depleted, NAPQI accumulates and causes hepatotoxicity. Acute toxicity from accidental ingestion is extremely rare in children. Paracetamol toxicity is more likely to be problematic in children taking standard doses of paracetamol chronically or in repeated supratherapeutic doses, rather than after a single ingestion.

Children appear less sensitive to the hepatotoxic effects of acute paracetamol overdose than adults. This may be related to metabolic differences, age-related clearance rates and to the increased propensity for children to vomit after acute paracetamol ingestion. The peak serum concentration is reached in <2 hours in the majority of children having a single ingestion of paracetamol elixir.

In the early phase, <24 hours, a child may be totally asymptomatic or complain only of mild abdominal pain, nausea and vomiting. Following a period of latency, hepatoxicity progresses to multiorgan failure. Paracetamol can directly cause renal impairment and coagulopathy with prolonged prothrombin time. The hepatorenal syndrome can also complicate severe hepatotoxicity. Finally, fulminant hepatic failure may occur or the patient may enter the recovery phase with return to normal hepatic function within 4 weeks. Rare consequences of paracetamol toxicity include myocardial necrosis, haemolytic anaemia, methaemoglobinaemia, skin rashes and pancreatitis.

In acute overdose, a serum level should be obtained 4 hours post-ingestion in all children with potential paracetamol ingestions of greater than 200 mg kg^–1. Children with acute single ingestions of liquid paracetamol preparations are likely to have reliable post-peak levels earlier than 4 hours post-ingestion – in these children, a 2-hour level above 1500 μmol L^–1 suggests risk of hepatotoxicity. Other relevant investigations include electrolytes, renal function, liver function tests and coagulation panel.

The paracetamol nomogram (Fig. 21.2.1), based on adult toxicity profiles, is extrapolated to children and predicts the potential for significant hepatotoxicity. The nomogram is applicable when a paracetamol level is taken between 4 and 16 hours post-acute ingestion. The nomogram cannot be utilised when the time of ingestion is unknown or in the case of staggered or chronic ingestions. Paracetamol treatment guidelines were reviewed by a representative panel of Clinical Toxicologists to the Australasian Poisons Information Centres and published in 2008. A major shift in management was the amalgamation of the high- and low-risk nomogram treatment lines into a single curve for both adults and children. This current line commences at 1000 μmol L^–1 at 4 hours post-ingestion and has a half-life of 4 hours.

Fig. 21.2.1 Paracetamol nomogram.

N-acetylcysteine (NAC), a glutathione precursor, is the antidote of choice in paracetamol poisoning. NAC is indicated in the setting of acute paracetamol ingestion, where the measured paracetamol level falls above the nomogram treatment line. The full course involves a loading dose of 150 mg kg^–1 in dextrose over 15–60 minutes, followed by a second infusion of 50 mg kg^–1 over 4 hours, and finally a 100 mg kg^–1 infusion over 16 hours. NAC is preferably commenced within 8 hours of ingestion, but has been documented to be effective in adult patients when given up to 48 hours after a serious ingestion, and can even be considered later when hepatic failure is established. Anaphylactoid reactions, including rash, bronchospasm, pruritus, hypotension and tachycardia, occur in up to 15% of cases, and are most common during the second infusion. These reactions are managed similarly to other hypersensitivity reactions; the NAC infusion should be temporarily ceased and recommenced at half the rate.

As children usually ingest the elixir formulation rather than tablets, rapid absorption precludes the utility of oral activated charcoal. Activated charcoal can be administered for potentially toxic doses of the tablet formulation, if given within 1 hour. Children who present with established hepatic failure must receive prompt resuscitation and stabilisation. NAC is still indicated when hepatotoxicity is established. Coagulopathy and encephalopathy should be managed as from other causes of liver failure. These children are managed in the intensive care and should be assessed for potential liver transplantation.

Chronic over-dosing or repeated supratherapeutic ingestion is a significant problem. The treatment nomogram is not applicable to these situations and cases should be discussed with a toxicologist. Children with paracetamol levels below the nomogram treatment line after acute single ingestions can be cleared from a toxicological point of view. Parents or carers should be educated on correct paracetamol dosing and safe storage. Children with deliberate self-poisoning should be assessed by the mental health team.

NSAIDs

Of the many non-steroidal anti-inflammatory drugs (NSAIDs) available, some obtainable as over-the-counter medicines without prescription, ibuprofen is the most significant NSAID ingested by children. As a group NSAIDs are generally of low toxicity, producing gastrointestinal upset, headache, dizziness, tinnitus, and visual disturbance. Hypotension, tachycardia, and hypothermia and coagulopathy have been reported when NSAIDs were consumed in large amounts. In massive overdose, electrolyte disturbances, metabolic acidosis, central nervous system depression, and respiratory failure can occur.

Asymptomatic children can be discharged at 4 hours post-ingestion. Symptomatic children require hospital admission. Oral fluids should be encouraged and dehydration corrected. Electrolytes, blood sugar level, renal function and acid–base status should be monitored. Activated charcoal may be indicated in massive ingestions that present early. Methods of enhanced elimination are not usually beneficial.

Benzodiazepines

Benzodiazepine overdose is commonly seen in toddlers who ingest 1–2 tablets, or as part of a mixed overdose in adolescents. Benzodiazepines bind predominantly to the γ-aminobutyric acid (GABA) type-A receptor complex in the central nervous system (CNS) and enhance GABA activity to produce sedative, anxiolytic and anticonvulsant activity. The duration of sedation ranges from 4–36 hours, depending on the agent. Flumazenil is a competitive antagonist at benzodiazepine receptors. Drowsiness, slurred speech and ataxia are the most common manifestations. This may progress to coma and hypotension, hypothermia and respiratory depression in more significant ingestions. Death is rare unless other CNS depressants have been co-ingested.

Management is entirely supportive. Hypotension usually responds to fluid administration. GI decontamination is not indicated in pure benzodiazepine poisoning. A blood sugar level should be checked in all children with an altered level of consciousness. Other laboratory investigations are not routinely indicated. Chest radiography is only indicated if aspiration is suspected. A qualitative urine test for benzodiazepines may provide reassurance as to the aetiology of drowsiness in the setting of an unconscious patient without a clear history of ingestion. In some clinical scenarios, flumazenil may avert the need for intubation and mechanical support but its use should be discussed with a toxicologist. Flumazenil should be administered in boluses of 5–10 mcg kg^-1 and titrated to clinical effect (respiratory rate and effort).

Most children can be discharged after 4–6 hours if vital signs are satisfactory and the child can walk unaided.

Opioids

Opioids are frequently available where family members suffer chronic pain, abuse drugs or are on drug-rehabilitation programmes. Iatrogenic intravenous overdosing of children is commonly a result of 10-fold errors in dose calculation.

Morphine and codeine are natural opium alkaloids. Other opioids are synthetic or semisynthetic analogues. The opioids act on various receptors on the brain, spinal cord and gastrointestinal tract as full or partial agonists or antagonists. Opioids are well absorbed by all routes except skin, are metabolised by the liver and are renally excreted. Some opioids (e.g. pethidine and diphenoxylate) have potent metabolites. Opioids vary in their duration of action and some are available as sustained release preparations (e.g. morphine). Toxicity is enhanced by co-ingestion of other sedative medications, which may be found in some cough remedies or analgesic preparations. Children are especially sensitive to the depressive effects of opioids.

Paediatric overdose of a parent’s methadone (long-acting opioid) syrup requires overnight admission for extended observation and monitoring. Antidiarrhoeal preparations contain diphenoxylate (with atropine) and produce delayed onset of symptoms, with numerous paediatric deaths reported. A major metabolite of diphenoxylate is more potent than the parent compound and undergoes enterohepatic circulation. Dextropropoxyphene has a membrane-stabilising effect on cardiac conducting tissue and may induce ventricular arrhythmias and heart block.

The classic features are of nausea and vomiting, drowsiness, pinpoint pupils, respiratory depression, and occasionally bradycardia and hypotension. Respiratory depression may lead to hypoxia and respiratory arrest. The histamine-releasing effects of some opioids may cause urticaria and hypotension.

Management of the opioid toxidrome is essentially supportive, with attention to airway and ventilation. All children with altered level of consciousness should have a blood sugar level checked. Activated charcoal may be considered for massive ingestions or long-acting preparations. Insertion of gastric tubes for charcoal administration is not recommended unless the child is intubated for other indications.

Naloxone, the antidote for opiate toxicity, is a competitive antagonist at opioid receptors. Naloxone (intravenously (IV) 0.01 mg kg⁻¹, maximum 2 mg, as a bolus, repeated every few minutes till appropriate response) may be useful to reverse the neurological and respiratory depression, and should be titrated to respiratory rate and effort. Naloxone’s short therapeutic half-life of 30–60 minutes may necessitate a continuous infusion, in order to maintain the reversal and obviate the need for mechanical ventilation, particularly for ingestions of long-acting opiates.

All patients should be observed for a minimum of 6 hours. Methadone, dextropropoxyphene and sustained-release morphine sulfate may cause symptoms persisting for 24–48 hours so prolonged observation is necessary after ingestion of these agents.

Anticholinergics and antihistamines

Anticholinergic (antimuscarinic) poisoning can result from a diverse range of therapeutic substances, plants and natural remedies, many of which can be bought over the counter. Pharmaceuticals with prominent anticholinergic properties include first-generation antihistamines, antipsychotics and tricyclic antidepressants. Some plants, e.g. Jimsonweed, angel’s trumpet, and mushrooms contain alkaloids with potent anticholinergic effects.

The anticholinergic toxidrome is caused by competitive inhibition of the muscarinic receptor in the autonomic nervous system. The classic anticholinergic toxidrome is well described by the following rhyme:

Other anticholinergic effects include tachycardia, gastrointestinal ileus and urinary retention.

The management of anticholinergic poisoning includes attention to the ABCs with appropriate supportive therapy and monitoring of vital signs and mental state. Symptomatic patients should have IV access, a 12-lead electrocardiogram (ECG) and continuous cardiac monitoring. Benzodiazepines are useful in managing agitation or seizures. Physostigmine is a cholinesterase inhibitor which enters the CNS and is effective at reversing central anticholinergic delirium. Due to concerns regarding adverse cardiac side effects, the use of physostigmine should be discussed with a toxicologist. The initial dose in children is 0.02 mg kg⁻¹ (maximum 0.5 mg) by slow IV push; doses may be repeated every 15 minutes.

Aggressive cooling measures may be required in severe hyperthermia. Urinary catheterisation is required for patients with urinary retention. Asymptomatic patients may be discharged after 6 hours. Patients with moderate or severe toxicity should be admitted to an intensive-care facility.

Antihistamine poisoning in children is of concern only for first-generation agents (e.g. promethazine), which have significant anticholinergic effects. Children should be observed for a minimum of 6 hours following ingestion. Management is supportive and the anticholinergic effects of antihistamines, while unpleasant, are generally not life threatening.

Hypotension should be treated with intravenous fluids. Convulsions and anticholinergic delirium are best managed with benzodiazepines. Continuous ECG monitoring is advised for symptomatic children and those with persistent tachycardia. Ventricular arrhythmias should be managed with sodium bicarbonate as the drug of choice for QRS prolongation with sodium-channel blocking antihistamines.

Corrosive ingestions

Most serious caustic ingestions involve strong acids and alkalis which account for a high number of presentations to the ED. The initial presentation and treatment are similar to other burns. Domestic bleaches and ammonia products generally cause minor injuries. Serious injuries result most often from the ingestion of drain and oven cleaners (NaOH, KOH). Dishwashing powder residue left in the dispenser of machines is a commonly accessed alkali that may cause serious injury.

The severity of burn depends on the nature, volume, pH and concentration of the agent and the duration of contact. Stomach contents may afford some protection from injury, but pylorospasm, oesophageal reflux and vomiting may exacerbate injury. Liquids may cause a circumferential injury and powders/granules or tablets may cause prolonged contact with a mucosal surface, with potential for linear burns, deep erosion and penetration. Acids cause superficial corrosion and a coagulative necrosis, and the extent of tissue penetration is limited by eschar formation. Alkalis start to burn immediately on contact and cause a liquefaction necrosis of fat and protein, penetrating deeply into tissues. Acids typically injure the stomach while alkalis damage the oropharynx and oesophagus.

Many children will be asymptomatic, especially if low-concentration household products are involved. Pain, drooling, dysphagia, vomiting and abdominal pain and haematemesis may occur. Airway compromise with laryngeal oedema, cough and bronchospasm may be seen after ingestion of high-concentration agents. Endoscopy provides the best guide to prognosis and management. The extent of injury is graded by the depth of ulceration and the presence of necrosis. Typically, after ingestion the mouth or oesophagus is red and ulceration follows within 24 hours. One-third of patients with oral burns have associated oesophageal lesions, whereas 10–15% of patients with oesophageal lesions have no oropharyngeal burns. Asymptomatic patients with no oral burns may have significant oesophageal injuries. Drooling and dysphagia persisting beyond 12–24 hours are reliable predictors for oesophageal scar formation and suggest the need for upper GI endoscopy.

Oesophageal perforation and mediastinitis may be suspected by chest pain, fever, pleural rub, dyspnoea. Abdominal pain, fever, peritonism and ileus may indicate gastric or abdominal oesophageal perforation. These signs may progress to septic shock, multiorgan failure and death. Large acid ingestions may be associated with hypotension, metabolic acidosis, haemolysis, nephrotoxicity and pulmonary oedema.

Late complications are infection, achlorhydria and stricture formation in 1–3%. All patients with full-thickness and 70% with deep ulceration will develop strictures. Eighty percent of all strictures occur within 2 months of ingestion and 99% within 1 year.

The management of caustic ingestions is aimed at limiting the extent of injury and preventing strictures and other complications. Immediate management consists of rinsing the skin with water or drinking water unless respiratory distress is notable or visceral perforation is suspected. Acids and alkalis do not bind to charcoal. Attempts to neutralise the substance are contraindicated, but dilution with water may possibly be helpful for acids and may reduce mucosal contact time in ingestion with particulate alkalis. Early treatment focuses on ensuring an adequate airway, intravenous fluid replacement, monitoring fluid balance, avoiding vomiting and adequate analgesia. Oesophagoscopy in the symptomatic patient guides further management. Patients with deep, especially circumferential burns of the oesophagus should be admitted to an intensive care unit and may require prolonged parenteral feeding and repeated endoscopic stricture dilatations. Early surgical intervention and prophylactic antibiotics are required if perforation or penetration is suspected clinically, on endoscopy or contrast radiography. Steroids have no proven benefit and may possibly increase the risk of perforation.

Asymptomatic patients should be advised to return if they develop respiratory difficulty, pain or dysphagia. All symptomatic children should be admitted for observation and potential endoscopy.

Ethanol

Ethanol is available in numerous household medicinals, mouthwashes and perfumery products as well as alcoholic drinks. All products marketed in Australia as ‘methylated spirits’ contain ethanol. Although frequently ingested by children, serious toxicity is uncommon.

Ethanol is well absorbed across gastrointestinal mucosa and respiratory tract, most within 30–60 minutes, and distributes to total body water. Children metabolise alcohol faster than adults. Only very small amounts are excreted unchanged in the urine and the breath. Hypoglycaemia is caused by depressed gluconeogenesis. The potentially fatal dose of alcohol for children is 4 mL kg⁻¹ of absolute alcohol (e.g. 10 mL kg⁻¹ for a 40% alcohol spirit), about half the dose required for adults. Quite low serum levels (>10 mmol L⁻¹, >0.05% or >500 mg L⁻¹) may produce clinically significant effects in children.

Ethanol acts on the reticular activating system to cause CNS depression. Low concentrations result in alterations of mood and thought processes, whereas higher concentrations affect cerebellar function, causing ataxia and slurred speech. Higher levels still depress all cortical function and brainstem activity, depressing respiratory drive and protective airway reflexes. Respiratory arrest or aspiration is a frequent cause of death. Facial flushing, excessive sweating and vomiting are common.

Management depends on the time elapsed since ingestion. Assess and secure the ABCs and correct electrolyte abnormalities and dehydration. Patients with severe CNS depression are at risk of aspiration and require airway protection. Blood glucose should be monitored. A blood alcohol level may be taken at least 1 hour post-ingestion if symptoms are present, although management is generally determined by the clinical state. Hypoglycaemia should be corrected with 5 mL kg⁻¹ 10% dextrose. Hypotension will usually respond to intravenous fluids and acidosis usually responds to correction of hypovolaemia and hypoglycaemia. Hypothermia should be corrected. Activated charcoal does not bind ethanol but may be considered if co-ingestants are suspected, provided the airway is protected. Gastric lavage is likely to be ineffective due to the rapid absorption from the stomach. Haemodialysis may be indicated in the extremely intoxicated child who is haemodynamically unstable, but this is uncommon. Admit all children who are clinically intoxicated until asymptomatic.