Nitrate Overdose

Medicinal nitrate overdose, with glyceryl trinitrate, isosorbide mononitrate or isosorbide dinitrate, causes vasodilatation, hypotension, headache, flushing and, in large ingestions or with interacting drugs, methaemoglobinaemia. Severe hypotension occurs with phosphodiesterase type 5 inhibitor co-use.

Overdose is uncommon and usually mild. Serious toxicity is possible with ingestions of more than 1 g of isosorbide, with large doses of sublingual glyceryl trinitrate, and when nitrates are combined with sildenafil, tadalafil or vardenafil.

Risk factors for harm. Co-use of phosphodiesterase type 5 inhibitors, hypovolaemia, aortic stenosis, severe anaemia and G6PD deficiency (for methylene blue).

Course. Onset within minutes (sublingual) to 1 to 2 hours (oral). Effects last 2 to 8 hours (up to 12 hours for modified release isosorbide).

Pathophysiology.

Nitrates release nitric oxide, which increases cyclic GMP in vascular smooth muscle and causes venous and arterial dilatation, while at high doses nitrite oxidises haemoglobin to methaemoglobin.

Phosphodiesterase type 5 inhibitors block breakdown of cyclic GMP, producing profound vasodilatation.

• Throbbing headache, flushing, dizziness, palpitations and reflex tachycardia.
• Hypotension, syncope and, in severe cases, shock.
• Methaemoglobinaemia: cyanosis not corrected by oxygen, chocolate coloured blood, dyspnoea, headache and confusion.
• Raised intracranial pressure effects and convulsions are rare.

Red flags.

• Systolic blood pressure under 90 mmHg or syncope.
• Cyanosis with normal arterial oxygen tension, or methaemoglobin over 20%.
• Co-ingestion of sildenafil, tadalafil or vardenafil.

• History of agent, dose, formulation and co-ingested drugs (phosphodiesterase type 5 inhibitors, other antihypertensives).
• Blood pressure, ECG, glucose and electrolytes; venous gas with co-oximetry for methaemoglobin (pulse oximetry is unreliable, usually reading about 85%).
• Lactate, renal function and troponin if chest pain or shock.

Differential diagnosis. Other antihypertensive overdose, anaphylaxis, sepsis, sulphaemoglobinaemia, and methaemoglobinaemia from dapsone, nitrites or local anaesthetics.

• Lie flat with legs raised, give oxygen and intravenous 0.9% sodium chloride 10 to 20 mL/kg for hypotension.
• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour of a large ingestion if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Persistent hypotension: noradrenaline 0.05 micrograms/kg/minute intravenously, titrated to a mean arterial pressure of 65 mmHg or higher. Maximum 1 microgram/kg/minute. Give by central line; monitor blood pressure, extravasation and arrhythmia.
• Methaemoglobinaemia over 20%, or any level with symptoms or hypoxia: methylene blue 1 to 2 mg/kg (1% solution) intravenously over 5 minutes, repeated once after 30 to 60 minutes if needed. Maximum 7 mg/kg in total. Monitor methaemoglobin by co-oximetry, blood pressure and haemolysis; high doses cause paradoxical methaemoglobinaemia. Avoid in G6PD deficiency, with serotonergic drugs (serotonin toxicity), and in renal failure (use caution); avoid in pregnancy unless essential.
• Phosphodiesterase type 5 inhibitor co-ingestion: supportive care; extend observation to 12 to 24 hours.
• Avoid further nitrates and phosphodiesterase type 5 inhibitors for 24 to 48 hours.
• Observe for at least 6 hours (12 hours for modified release or large ingestions), with normal blood pressure and methaemoglobin before discharge.
• Psychiatric assessment in intentional ingestion.

Monitoring. Blood pressure, heart rate, oxygen saturation and methaemoglobin level; lactate in shock.

Referral and escalation. Poisons information centre; intensive care for refractory shock or methaemoglobinaemia not responding.

Special groups. Children: methaemoglobinaemia occurs more readily in infants. G6PD deficiency: avoid methylene blue and use exchange transfusion or ascorbic acid by specialist advice.