Theophylline toxicity can be life-threatening, resulting in both central nervous system and cardiovascular system over-stimulation. Management includes early gastrointestinal decontamination and prevention and treatment of seizures and arrhythmias.

Fortunately, given the availability of alternative agents and its recognised narrow therapeutic range, theophylline use has become rare meaning toxicity is now uncommon.

Adenosine Receptor Antagonism
Adenosine acts as an inhibitory neurotransmitter, with blockade of adenosine receptors leading to uncontrolled excitatory neurotransmission, including seizures. Similarly, adenosine normally slows cardiac conduction, with blockade of receptors leading to tachyarrhythmia and increased automaticity.

Catecholamine Release
Dose related increases in catecholamine concentrations occur with both therapeutic and toxic concentrations of theophylline. The resultant excess adrenergic stimulation leads to tachycardia, hypertension (early), hypotension via β2 effects (late) and metabolic derangement (hyperglycaemia, hypokalaemia, lactic acidosis).

Phosphodiesterase inhibition
At toxic concentrations theophylline causes inhibition of phosphodiesterase with resultant cAMP accumulation. Excess cAMP leads to cardiac stimulation with tachycardia and arrhythmias, vasodilation leading to hypotension and increased neuronal excitability resulting in seizures.

Theophylline has a narrow therapeutic range, and signs of toxicity can develop with any supratherapeutic ingestion (>10mg/kg).

Ingestions of >30mg/kg are expected to cause more significant signs of toxicity and those >50mg/kg are associated with severe life-threatening toxicity.

Children can develop toxicity from small accidental ingestions with a single 200mg modified-release tablet potentially leading to toxicity in a 10kg child.

Risk assessment based on serum concentration after acute ingestion:

Chronic toxicity can occur due to prolonged supratherapeutic use or, more commonly, following intercurrent illness that changes the pharmacokinetics of theophylline. The relationship between toxicity seen and serum concentration is less well correlated in chronic toxicity but levels >220 µmol/L (>40 mg/L) are associated with more major manifestations.

Immediate-release preparations exhibit virtually complete and rapid absorption (peak concentrations 0.5-2 h).

With sustained release preparations, the peak concentration usually occurs between 2 and 18 hours after administration but can occur as late as 24 hours post ingestion.

The mean apparent volume of distribution for theophylline is 0.5 L/kg.

The pharmacokinetics of theophylline may be affected by hepatic, cardiac or renal disease, leading to variability in toxicity seen following a given dose ingested or given plasma level.

In therapeutic use theophylline clearance is 40-45 mL/kg/hr giving a half-life of approximately 8 hours. In overdose, hepatic metabolism of theophylline is commonly saturated and the apparent half-life can be as long as 30 hours.

Theophylline toxicity largely manifests as excessive catecholamine stimulation and therefore gives a similar clinical presentation to the sympathomimetic toxidrome.

• Cardiovascular effects: Tachycardia, ectopy, hypertension (early), hypotension (late), supraventricular and ventricular arrhythmias, cardiac ischaemia.
• CNS effects: Agitation, tremor, hyperreflexia, seizures.
• Gastrointestinal: Nausea, vomiting.
• Metabolic effects: Hyperglycaemia, hypokalaemia, metabolic acidosis, hypercalcaemia, respiratory alkalosis (hyperventilation).

• ECG: Most patients will have a degree of tachycardia and may develop both atrial and ventricular arrhythmias. Excess cardiac stimulation may lead to cardiac ischaemia.
• Serum theophylline concentrations: Measure every 2-4 hours, may see double peak due to erratic absorption in overdose.
• Serum electrolytes: patients are at risk of electrolyte derangement (especially hypokalaemia, hypercalcaemia and hyperglycaemia.
• Bloods gas analysis: Lactic acidosis often develops.

Similar presentation maybe be seen following ingestion of agents with sympathomimetic effects including:

• Caffeine
• Recreational stimulants e.g. methamphetamines
• Prescription stimulants e.g. dexamphetamines
• Serotonin-noradrenaline reuptake inhibitors e.g. venlafaxine

Airway and Breathing
Theophylline toxicity is not expected to directly compromise airway and breathing but compromise may occur secondary to seizures, especially if refractory. If compromise occurs, intubate and ventilate patient.

Circulation
Patients admitted for theophylline toxicity should remain on cardiac monitoring to identify the onset of arrhythmias.

Hypotension is common, especially if dehydration is present, which occurs due to toxicity induced vomiting. Start all patients of IV fluids to maintain hydration.

If hypotension develops, this is normally related to beta-adrenal vasodilation and should initially be treated with intravenous fluid resuscitation. If hypotension is resistant to fluid resuscitation, then start a vasopressor. Use:

Adults: Noradrenaline 3 to 50mcg/minute titrated to desired blood pressure target
Children: Noradrenaline 0.05 to 1 mcg/kg/minute titrated to desired bloods pressure target

If escalating doses of vasopressors are required, then get expert advice from a clinical toxicologist regarding further treatment including other vasopressors or beta blockade.

Seizures
The onset of seizures is often heralded by agitation. If agitation occurs, provided sedation with benzodiazepines until the patient is sedated but rousable.

If seizures occur, they may be refractory, treat promptly with intravenous benzodiazepine; escalate to barbiturates if control is not achieved with benzodiazepines.

Vomiting
Vomiting is seen in all cases of toxicity and can be resistant to treatment. Treat along standard lines, multiple different agents are likely to be needed.

Hypokalaemia
Hypokalaemia occurs mainly due to intracellular potassium shift but also GI losses due to vomiting. Monitor serum potassium concentration and replaced to normal levels.

Activated Charcoal
Offer activated charcoal to patients ingesting >10mg/kg theophylline, if they are alert, co-operative and able to protect their airway. For immediate release preparations offer up to 2 hours post ingestion, in sustained release ingestions offer up to 4-hour post ingestion.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)

Whole Bowel Irrigation
Consider whole bowel irrigation for patients presenting following ingestion of >30mg/kg sustained release theophylline. If undertaking whole bowel irrigation (link), give activated charcoal regardless of time since ingestion.

Multi-dose activated charcoal
Multi-dose activated charcoal has been shown to significantly increase the elimination of theophylline and should be considered in patients who have taken >30mg/kg theophylline and have an elevated theophylline level.

Haemodialysis
Haemodialysis can increase theophylline clearance 1.5-2 times. Charcoal hemoperfusion is often stated as being more effective than conventional dialysis, however this was based on older data with comparison to dialysis circuits using much lower efficiency filters and the difference is likely small with curent equiptment. Charcoal haemoperfusion is less readily available and associated with greater risk of complications (coagulopathy, electrolyte disturbances).

Consider haemodialysis in theophylline toxicity if:

• Serum concentration is > 550 µmol/L (>100 mg/L) in acute poisoning
• Serum concentration is > 330 µmol/L (>60 mg/L) in chronic poisoning
• Features of severe toxicity are present (e.g. refractory seizures, life-threatening arrhythmias, cardiovascular shock, increasing levels despite optimal care).

There is no specific antidote for the treatment of theophylline toxicity.

Patients ingesting >30mg/kg theophylline should be admitted for 24 hours for observations for the onset of toxicity.

Discharge those ingesting <30 mg/kg if they have no signs of toxicity and and normal ECG at 6 hours following an immediate release ingestion or 12 hours following a modified release ingestion.

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