• Use of nebulised iloprost or epoprostenol should only be on consultant intensivist recommendation after conventional treatment for severe ARDS has failed and the rationale documented in the notes.

• Treatment must be reviewed daily and discontinued if no improvement, or the dose reduced when improvement is sustained.

• Treatment is not to be continued once the patient leaves ICU.

• This is an off-label use of these drugs.

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Abbreviations

Nebulised iloprost or epoprostenol were recommended for off-label use for refractory COVID-19 associated acute respiratory distress syndrome (ARDS) in line with NHS England guidance. They are also recommended at times by tertiary centres for patients with refractory ARDS.

When administered by nebulisation they can act as a pulmonary vasodilator which may be of benefit in patients with hypoxaemia due to ARDS or in patients with high pulmonary vascular resistance.

Nebulised iloprost and epopostenol (both prostacyclins) reduce PaO₂/FiO₂ ratio in patients with ARDS with a reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and increase in cardiac output (CO). This leads to an improvement in venous and arterial oxygenation. It is unknown whether nebulised prostacyclins reduce the risk of mortality and no current evidence supports or refutes the routine use of aerosolized prostacyclin for people with ARDS. Evidence is limited to small trials and larger RCT are needed.

• ICU consultant recommendation needed and rationale for use documented in the notes.

• Pulmonary hypertension secondary to severe ARDS, with hypoxemia that is refractory to standard therapies where non-systemic treatment is needed. Consideration should have been made for proning the patient.

• Patients with ARDS who also have decompensated or acute pulmonary arterial hypertension and right heart dysfunction.

• Hypersensitivity to the active substance or to any of the excipients

• Conditions where the effects of prostaglandins on platelets might increase the risk of haemorrhage (e.g., active peptic ulcers, trauma, intracranial haemorrhage).

• Severe coronary heart disease or unstable angina.

• Myocardial infarction within the last six months.

• Decompensated cardiac failure if not under close medical supervision.

• Severe arrhythmias.

• Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last 3 months.

• Pulmonary hypertension due to venous occlusive disease.

• Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension.

Hypotension (SPC states iloprost must not be initiated if SBP <85mmHg)

Benefits vs risks should be considered in pregnant patients and rationale be documented in the medical notes.

• Bleeding – epistaxis, haemoptysis

• Tachycardia or bradycardia

• Facial flushing

• Headache

• Hypotension (which may necessitate a dose reduction to the maximum tolerated dose)

• Cough / bronchospasm

Targets should be set for therapy. Improvements in Cardiac output, PaO₂ and O₂ saturations (and pulmonary artery pressure if available) should guide dose adjustments. If no improvement is seen therapy should be discontinued after 24-48 hours of treatment.

Assessment of the extent of pulmonary hypertension is ideal using a pulmonary artery catheter however this must be balanced against practicalities or availability of such measurements. If not possible, then cardiac output monitoring should be performed using Lidco®.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Should signs of pulmonary oedema occur, the possibility of associated pulmonary veno-occlusive disease should be considered and treatment with iloprost should be discontinued.

If the ventilated patient has cardiovascular insufficiency nebulised epoprostenol may be the preferred nebulised prostaglandin due to a shorter half-life.

Due to the agents being prostacyclin analogues, there is a theoretical risk to the unborn child of pregnant staff. Pregnant staff should not be exposed to nebulised iloprost or epoprostenol.

Iloprost

Dose

10 – 20 micrograms (1-2ml) solution up to every 2 hours by nebulisation using an Aerogen® nebuliser system

Iloprost should only be nebulised in a closed circuit having a bacterial/viral micro filter attached on the exhalation tube. It should not be mixed with other preparations.

The maximal clinical effect is achieved 15 minutes after completing inhalation. Therapy should be discontinued if improvement in CO, PaO₂ or reduction in PAP is not achieved after 24-48 hours of therapy.

Epoprostenol

Preparation

Reconstitute the powder by adding a 10mL of the solvent provided to the 500microgram epoprostenol vial.

Shake gently until the powder has dissolved.

Draw up the reconstituted solution and inject it into the remaining volume of solvent. Mix well.

This contains 500microgram in 50mL (10micrograms/mL = 10,000nanograms/mL)

The solution expires after 24 hours at room temperature if using the Flolan®­­­ brand, but this may vary for generic preparations in which case product literature should be consulted.

Commence nebulisation via Aerogen® syringe driver at prescribed rate.

The filter in the expiratory limb of the circuit is likely to become saturated with glycine from the nebulised solution, which can increase expiratory pressures. Filters must therefore be regularly changed whilst on nebulised epoprostenol.

It is recommended that expiratory filters are changed at a minimum of every 8 hours.

Elevated PEEPs may indicate that filters be changed sooner, which is likely to occur at delivery rates over 10mL/hour.

There have been reports of epoprostenol infusions eroding connectors when used during renal replacement therapy; the lines and connectors should be checked at each syringe change to ensure patency.

Start the nebulised epoprostenol at 10 nanograms/kg/minute based on the patient’s ideal body weight. This may be increased to 30 nanograms/kg/minute however some sources do use a range of 5 - 50 nanogram/kg/minute based on ideal body weight; titrate by increasing or decreasing dose in increments of 10 nanograms/kg/minute every 30 minutes to 2 hours as tolerated based on clinical response. Titrate to lowest effective dose based on response. In practice higher doses are limited by the nebuliser delivery rate.

Avoid abrupt withdrawal as this can cause rebound pulmonary hypertension.

Reduce the delivery rate by 50% every hour until it has been running at less than 5mL/hour for 1 hour when it can then be stopped.

To administer a dose of 20 nanograms/kg/minute of nebulised epoprostenol to a patient with an ideal body weight of 70kg using a standard solution of 500micrograms in 50mL (10 micrograms/1mL = 10,000 nanograms/1mL):

Nebulised epoprostenol rate (mL/hour) = 20 nanograms/kg/min x 60mins x 70kg = 8.4 mL/hour

10,000 nanograms in 1mL

Rate (mL per hour) of delivery of epoprostenol 500micrograms in 50mL (10micrograms in 1ml) required for different patient weights:

† 12mL/hour is the maximum rate of delivery into the Aerogen® nebuliser