Drug group	Examples
Alcohols	Ethanol, methanol, isopropyl glycol, ethylene glycol
Metals	Lithium, iron, mercury, potassium, lead, arsenic
Acids and alkalis
Hydrocarbons	Turpentine, kerosene, eucalyptus oil, benzene

Elimination

There are several forms of enhanced elimination that are more commonly used depending on the type of overdose. Again, assess the severity of the toxicity to determine whether employing these techniques will be beneficial.

Multiple doses of charcoal may decrease drug absorption in some cases (Box 28.2). A suggested dosing regimen would be 25 g (adults) or 0.5 g/kg (children) every 2–4 hours. It is contraindicated if there is a bowel obstruction or decreased level of consciousness in a patient without a protected airway. Always check for the presence of bowel sounds before administering the next dose.

Box 28.2 Situations when multiple doses of charcoal may reduce drug absorption

Ingestion involves large amounts or formation of concretions/bezoars.

Drugs are enteric-coated or slow-release.

Reabsorption (e.g. via enterohepatic circulation) can be prevented.

Stomach emptying is delayed (e.g. anticholinergic effects). Ensure the presence of bowel sounds prior to repeating dose of charcoal as ileus can occur due to anticholinergic effects.

The drug involved is carbamazepine, dapsone, phenobarbitone, quinine or theophylline.

Urinary alkalinisation may be used for increasing elimination of weak acids. This can be achieved by intravenous administration of sodium bicarbonate. Give a bolus of 1 mmol/kg IV followed by an infusion (100 mmol of sodium bicarbonate in 1000 mL 5% dextrose in 0.9% saline over 4 hours). Adjust the rate to a urinary pH > 7.5. Complications of bicarbonate therapy include fluid overload, alkalaemia, hypokalaemia and hypocalcaemia. Main indication is salicylate overdose.

Whole bowel irrigation with agents such as polyethylene glycol is rarely used. It hastens the elimination of poorly absorbed or slow-release medications before they can be absorbed. Complications include vomiting, abdominal bloating and pain. Rarely colonic or oesophageal perforation has been reported as well as GI bleeding (Mallory-Weiss tear) and aspiration pneumonia after vomiting.

Dialysis is the most commonly used form of extracorporeal elimination. It can enhance elimination of various toxins (Box 28.3). Indications for dialysis are listed in Box 28.4.

Box 28.3 Drugs amenable to dialysis

Box 28.4 Indications for dialysis

Failure to respond to full supportive methods

Inability to excrete or metabolise drug due to impaired route of elimination (e.g. renal failure, hepatic failure)

Associated metabolic abnormalities that would be resolved with dialysis (e.g. metformin lactic acidosis)

Specific therapies

Coma

• Reduced GCS is a common toxic effect of many drugs and poisons.

• Look for reversible causes and treat urgently—hypoglycaemia, opiate intoxication.

• Priority is focused on establishing a patent and finally a protected airway.

• If coma was not a predicted outcome of the overdose investigate for other causes.

Seizures

• Benzodiazepines are first-line therapies for drug-related seizures.

• Barbiturates are second-line.

• Phenytoin is not indicated.

• If seizures are atypical (focal or partial), further investigation of the seizure is warranted.

Cardiovascular instability

• Management of hypotension involves intravenous access and fluids. Treat any associated arrhythmias.

• Antidotes, specific therapies and inotropes may be indicated (calcium for calcium-channel blocker overdose, sodium bicarbonate for tricyclic, antidepressant overdose, inotropes for beta-blocker overdose).

Hyperthermia

• Hyperthermia has life-threatening consequences such as multi-organ failure.

• Aggressive early treatment is essential.

• Cooled fluids, cooling blanket ± intubation, ventilation and paralysis are among the treatment options.

• Continuously monitor core temperature (rectal/bladder).

Metabolic and cognitive disturbances

• Screen for and treat conditions such as hypoxia, hypercarbia, glucose and acid–base and electrolyte abnormalities.

• Manage agitation and confusion initially with verbal reassurance and if unsuccessful use benzodiazepines (first-line) or olanzapine to achieve gentle sedation. Key aims include safety of the patient (prevention of absconding) and safety of the staff.

Antidotes

For a list of antidotes, see the ‘Quick reference’ section.

TOXIDROMES AND SPECIFIC OVERDOSES

The clinical presentation of some poisonings may be predictable based on the pharmacology of the drug/substance involved. Some classic toxidromes with examples are listed in Table 28.2.

Table 28.2 Some classic toxidromes

Benzodiazepines

Overdoses of benzodiazepines are common and have a good prognosis with supportive treatment. CNS and respiratory depression are the main toxic effects. Flumazenil may confirm the diagnosis but is generally not used for treatment, unless reversing iatrogenic conscious sedation or if advanced airway management is unavailable. The half-life of flumazenil (about 1 hour) is much shorter than that of all benzodiazepines; repeat doses of flumazenil may be required to maintain effect.

Key points—benzodiazepines

• Use flumazenil carefully in mixed overdoses as some co-ingestants (e.g. tricyclic antidepressants) may be proconvulsant and flumazenil may precipitate seizures and death.

• Other contraindications include known seizure disorder and benzodiazepine dependence.

Opioids

This group of drugs includes those derived from opium as well as those that have opiate-like activity. Typical toxic effects are CNS and respiratory depression and miosis. Acute lung injury has been reported, typically occurring once ventilation has been restored following a period of respiratory depression. Other effects include mild hypotension (arteriolar and venous vasodilation). Treatment of opioid toxicity is supportive, especially of the airway and ventilation, and sometimes involves the use of naloxone, either as bolus dose(s) or infusion. Several drugs in this group have atypical toxic effects (Table 28.3).

Table 28.3 Atypical opioids

Opioid	Atypical toxic effects of clinical significance
Tramadol	Serotonergic syndrome, seizures
Dextropropoxyphene	Seizures, wide QRS arrhythmias, negative inotropic effects (Na channel blockade)
Methadone	Prolonged QT interval (possibly → torsades de pointes)
Pethidine	Seizures
Fentanyl	Muscle rigidity (rapid injection)

Key points—opioids

• Check the duration of action of the opioid involved. Some are as short as several hours (fentanyl, heroin) and others as long as 24 hours (methadone and controlled-release forms of morphine and oxycodone). This may help to predict the likelihood of requiring a naloxone infusion and intensive care.

• Be mindful of more unusual routes of opioid administration such as transdermal patches (fentanyl).

• Naloxone can be life-saving. The treatment goal is adequate respiration as opposed to complete CNS recovery. Infusions can be used for the longer acting opioid intoxication.

• The effects of naloxone are seen within minutes when administered intravenously. Duration of action is short (0.5 hours). Depending on the opioid, observation for up to 12–24 hours after receiving naloxone may be required, as administration of the antidote may need to be repeated.

• Naloxone can precipitate severe opioid withdrawal in the tolerant patient. Reverse respiratory depression with small increments in order to prevent severe withdrawal.

• Buprenorphine is a partial agonist. In overdose, naloxone can be used to reverse respiratory depression but a partial or complete lack of response may be seen.

Paracetamol

Paracetamol overdoses can be either single or staggered ingestions. There are four described stages of paracetamol poisoning (Table 28.4). Stage II marks the onset of liver injury. Renal failure is seen in 25–50% of those with hepatic dysfunction. Death is usually due to multi-organ failure, sepsis, haemorrhage, acute respiratory distress syndrome and/or cerebral oedema. Key blood tests are paracetamol level and transaminases—aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Prothrombin time (PT) may also be indicated. Paracetamol levels are reported in various units (mg/L or μmol/L). When plotting the paracetamol level on the nomogram, always check the units are corresponding to the correct axis. Failure to do so may be life-threatening.

Table 28.4 Stages of paracetamol poisoning

Paracetamol can be implicated in an accidental overdose. Remember to ask quantities of paracetamol ingested in the patient who has been self-medicating to achieve analgesia. Paracetamol is a common component of over-the-counter medications such as cold and flu preparations and migraine tablets. Serious hepatotoxicity is less common in children compared to adults. Charcoal can be given in those who present within 1 hour after potentially toxic ingestions.

Key points—paracetamol

• Presentation > 8 hours after ingestion increases the likelihood of hepatic failure and death.

• N-acetylcysteine (NAC) should be commenced immediately if:

• time of ingestion is unknown

• there are signs of hepatic injury after any paracetamol overdose.

• Do not delay commencing NAC if > 8–24 hours after ingestion. The infusion can be ceased or continued once the paracetamol level and results of transaminases are analysed.

• Hepatotoxicity is unlikely if > 24 hours after ingestion has elapsed and transaminases are normal and paracetamol is undetectable.

• Guidelines for sustained-release products. If the total dose ingested is > 150 mg/kg start NAC immediately and take 4- and 8-hour paracetamol levels. Only cease NAC if both levels are below the line on the nomogram.

• Serial LFTs and PT are recommended in cases where NAC has been commenced in patients presenting 8 hours after ingestion.

• Increases in AST and ALT levels are frequently the first laboratory sign of liver injury in paracetamol toxicity. Hepatotoxicity is defined as an AST or ALT > 1000 IU/L. King’s College Criteria for paracetamol toxicity are predictors of poor prognosis. They are:

• pH <7.3 after adequate fluid resuscitation

• creatinine > 300 μmol/L

• prothrombin time > 100 seconds or international normalised ratio (INR) > 6.5

• grade III or IV encephalopathy.

• Early referral or consultation with liver transplantation services should be considered if any of the King’s College Criteria are present or worsening serial tests (↑ PT/INR or creatinine, ↓ pH and severe thrombocytopenia).

Guidelines and treatment nomogram

A recent collaboration of clinical toxicologists in Australia and New Zealand resulted in new guidelines and a new treatment nomogram published in the Medical Journal of Australia (March 2008). These are summarised below.

General key points

• There is a new treatment nomogram which lowers the old nomogram by 25%.

• Possible toxic doses:

• As a guide, > 200 mg/kg or 10 g (whichever is less) of paracetamol either as a single ingestion or staggered over a single 24-hour period in adults or children > 6 years may be associated with hepatic injury.

• As a guide, ≥ 200 mg/kg of paracetamol either as a single ingestion or staggered over a single 24-hour period in children aged 0–6 years may be associated with hepatic injury.

Management of acute single ingestions

Paracetamol levels measured > 4 hours post-ingestion can be plotted on a nomogram to determine risk of hepatotoxicity and indicate the need for N-acetylcysteine (NAC) therapy.

Presentation within 8 hours:

1. Measure the serum paracetamol (at 4–8 hours) and plot according to the nomogram. No other tests (e.g. LFTs, INR) are beneficial in making a risk assessment.

2. If the level is plotted above the treatment line, commence and complete NAC therapy. No further tests are required following completion of 20-hour NAC infusion.

3. If the level is plotted below the treatment line, then no further medical treatment is required.

Presentation 8 hours after ingestion:

1. NAC should be commenced immediately if:

• the reported dose is possibly toxic (see above)

• the patient shows signs of hepatic injury (nausea, vomiting, right upper quadrant pain or tenderness).

2. Measure serum paracetamol level and ALT.

• If the paracetamol level plots under the treatment line and the ALT is normal, stop NAC.

• If the paracetamol level plots under the treatment line and the ALT is raised, continue NAC. Measure ALT after completion of NAC. If ALT is normal, no further treatment is required. If ALT is abnormal, continue NAC and measure INR and platelet count.

• If the paracetamol level plots above the treatment line on the nomogram, continue NAC treatment and remeasure the ALT at the end of the infusion. If the ALT is normal, nothing further is required. If the ALT is raised, continue NAC and monitor INR and platelet count.

Management of staggered ingestions

• If it has been less than 8 hours since the first dose, treat as above (acute single ingestion presenting within 8 hours).

• If it has been more than 8 hours since the first dose, treat as above (acute single ingestion presenting after 8 hours).

Repeated supratherapeutic ingestion

1. If patient has ingested a possible toxic dose (see Table 28.5), measure serum paracetamol level and ALT.

2. If ALT is normal and the paracetamol level < 120 μmol/L (20 mg/L), no further treatment is required.

3. If there is any other result, commence NAC and repeat paracetamol level and ALT at 8 hours. If ALT is normal or static, no further treatment is required; if ALT is abnormal or worsening, continue NAC and check ALT at 12-hourly intervals.

Table 28.5 Repeated supratherapeutic doses that may be associated with hepatic injury

Adults and children aged > 6 years	Children aged < 6 years
> 200 mg/kg or 10 g (whichever is less) over a single 24-hour period	≥ 200 mg/kg over a single 24-hour period
150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48 hours	≥ 150 mg/kg per 24-hour period for the preceding 48 hours
> 100 mg/kg or 4 g/day (whichever is less) in patients with predisposing risk factors (e.g. chronic alcohol use, use of enzyme-inducing drugs, prolonged fasting, dehydration)	≥ 100 mg/kg per 24-hour period for the preceding 72 hours