Active Ingredient: Nitric oxide (NO)
Nitric oxide, in conjunction with ventilatory support and other appropriate active substances, is indicated as part of the treatment of peri- and post-operative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0-17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and 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 2 day(s)
10 [ppm]
5 [ppm]
Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracic anaesthesia & intensive care. Prescription should be limited to those cardio-thoracic units that have received adequate training in the use of a nitric oxide delivery system. Nitrous oxide should only be delivered according to an anaesthetist’s or intensive care physician’s prescription.
Nitrous oxide should be used only after conservative support has been optimised. In clinical trials nitrous oxide has been given in addition to other standard treatment regimes in the peri-operative setting, including inotropic and vasoactive medicinal products. nitrous oxide should be administered under close monitoring of haemodynamics and oxygenation.
The starting dose of inhaled nitric oxide is 10 ppm(part per million) of inhaled gas. The dose may be increased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose. Clinical data supporting the suggested dose in the age range 12-17 years is limited.
The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved oxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated after a minimum of 10 minutes. Consideration should be given to discontinuation of treatment if no beneficial physiological effects are apparent after a 30-minute trial of therapy. Treatment may be initiated at any time point in the peri-operative course to lower pulmonary pressure. In clinical studies treatment was often initiated before separation from Cardio Pulmonary Bypass. Inhaled NO has been given for time periods up to 7 days in the peri-operative setting, but common treatment times are 24-48 hours.
Attempts to wean nitrous oxide should be commenced as soon as the haemodynamics have stabilised in conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide therapy should be performed in a stepwise manner. The dose should be incrementally reduced to 1 ppm for 30 minutes with close observation of systemic and central pressure, and then turned off. Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of nitrous oxide. Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in pulmonary artery pressure with subsequent circulatory instability.
The safety and efficacy of nitrous oxide in premature infants less than 34 weeks of gestation has not yet been established. No recommendation or posology can be made.
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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