Active Ingredient: Nitric oxide (NO)
Nitric oxide, in conjunction with ventilatory support and other appropriate active substances, is indicated for the treatment of newborn infants ≥34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation.
For this indication, competent medicine agencies globally authorize below treatments:
Respiratory (Inhalation)
5 - 20 [ppm]
From 5 To 20 [ppm] once every day for 4 day(s)
20 [ppm]
5 [ppm]
Prescription of nitric oxide should be supervised by a physician experienced in neonatal intensive care. Prescription should be limited to those neonatal units that have received adequate training in the use of a nitric oxide delivery system. Nitric oxide should only be delivered according to a neonatologist’s prescription. nitric oxide should be used in ventilated newborn infants expected to require support >24 hours. Nitric oxide should be used only after respiratory support has been optimised. This includes optimising tidal volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end expiratory pressure).
The maximum recommended dose of nitric oxide is 20 ppm and this dose should not be exceeded. In the pivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hours of therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at this lower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement in the neonate’s oxygenation such that the FiO2 (fraction of inspired oxygen) <0.60.
Treatment can be maintained up to 96 hours or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from nitric oxide therapy. The duration of therapy is variable, but typically less than four days.
Attempts to wean nitric oxide should be made after the ventilator support is substantially decreased or after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, the dose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenation during administration of nitric oxide at 1 ppm, the FiO2 should be increased by 10%, the nitric oxide is discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20%, nitric oxide therapy should be resumed at 5 ppm and discontinuation of nitric oxide therapy should be reconsidered after 12 to 24 hours. Infants who cannot be weaned off nitric oxide by 4 days should undergo careful diagnostic work-up for other diseases.
For endotracheopulmonary use.
Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/air mixture using an approved (CE-marked) nitric oxide delivery system. Before initiation of therapy, during set-up, secure that the device setting is in agreement with the cylinder gas concentration.
The delivery system must provide a constant inhaled nitric oxide concentration irrespective of the ventilator. With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of nitric oxide into the inspiratory limb of the ventilator circuit. Intermittent flow neonatal ventilation may be associated with spikes in nitric oxide concentration. The nitric oxide delivery system for intermittent flow ventilation should be adequate to avoid spikes in nitric oxide concentration.
The inspired nitric oxide concentration must be measured continuously in the inspiratory limb of the circuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured at the same site using calibrated and approved (CE-marked) monitoring equipment. For patient safety, appropriate alarms must be set for nitric oxide (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 (± 0.05). The nitric oxide gas cylinder pressure must be displayed to allow timely gas cylinder replacement without inadvertent loss of therapy and backup gas cylinders must be available to provide timely replacement. Nitric oxide therapy must be available for manual ventilation such as suctioning, patient transport, and resuscitation.
In the event of a system failure or a wall-outlet power failure, a backup battery power supply and reserve nitric oxide delivery system should be available. The power supply for the monitoring equipment should be independent of the delivery device function.
The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker’s legislation is 25 ppm for 8 hours (30 mg/m³) in most countries and the corresponding limit for NO2 is 2-3 ppm (4-6 mg/m³).
The key elements that need to be covered in training hospital personnel are as follows.
Correct set-up and connections:
Operation:
Neonates and infants are known to have diminished MetHb reductase activity compared to adults.
Methaemoglobin level should be measured within one hour after initiation of nitric oxide therapy, using an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is >2.5%, the nitric oxide dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered. Although it is unusual for the methaemoglobin level to increase significantly if the first level is low, it is prudent to repeat methaemoglobin measurements every one to two days.
In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the initiation of nitric oxide therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the nitric oxide dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered.
Immediately prior to each patient initiation, proper procedure must be applied to purge the system of NO2. The NO2 concentration should be maintained as low as possible and always <0.5 ppm. If the NO2 is >0.5 ppm, the delivery system should be assessed for malfunction, the NO2 analyser should be recalibrated, and the nitric oxide and/or FiO2 should be reduced if possible. If there is an unexpected change in nitric oxide concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated.
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