Posology : מינונים

4.2 Posology and method of administration

Persistent Pulmonary Hypertension in the Newborn (PPHN)
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. Mixture NO 800 ppm in Nitrogen prescription.
Mixture NO 800 ppm in Nitrogen should be used in ventilated newborn infants expected to require support >24 hours. Mixture NO 800 ppm in Nitrogen should be used only after respiratory support has been optimized. This includes optimizing tidal volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end expiratory pressure).

Pulmonary hypertension associated with heart surgery
Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracic anesthesia & 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. Mixture NO 800 ppm in Nitrogen should only be delivered 

Posology
Persistent Pulmonary Hypertension in the Newborn (PPHN)
The maximum recommended dose of Mixture NO 800 ppm in Nitrogen 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 he 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 Mixture NO 800 ppm in Nitrogen therapy. The duration of therapy is variable, but typically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4.

Weaning
Attempts to wean Mixture NO 800 ppm in Nitrogen 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 Mixture NO 800 ppm in Nitrogen at 1 ppm, the FiO2 should be increased by 10 %, the Mixture system discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20 %, Mixture therapy should be resumed at 5 ppm and discontinuation of Mixture therapy should be reconsidered after 12 to 24 hours. Infants who cannot be weaned off Mixture sustem by 4 days should undergo careful diagnostic work-up for other diseases.

Pulmonary hypertension associated with heart surgery

Mixture NO 800 ppm in Nitrogen should be used only after conservative support has been optimized. In clinical trials Mixture NO 800 ppm in Nitrogen has been given in addition to other standard treatment regimes in the peri-operative setting, including inotropic and vasoactive medicinal products. Mixture NO 800 ppm in Nitrogen should be administered under close monitoring of haemodynamics and oxygenation.


Newborn infants, infants and toddlers, children and adolescents, ages 0-17 years 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.

Adults
The starting dose of inhaled nitric oxide is 20 ppm (part per million) of inhaled gas. The dose may be increased up to 40 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.
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.

Weaning

Attempts to wean Mixture NO 800 ppm in Nitrogen should be commenced as soon as the haemodynamics have stabilized 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 Mixture NO 800 ppm in Nitrogen. Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in pulmonary artery pressure with subsequent circulatory instability.

Paediatric population
The safety and efficacy of Mixture NO 800 ppm in Nitrogen in premature infants less than 34 weeks of gestation has not yet been established. Currently available data are described in section 5.1 but no recommendation or posology can be made.

Method of administration
For endotracheopulmonary use.
Mixture NO 800 ppm in Nitrogen 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 Mixture NO concentration irrespective of the ventilator.
With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of Mixture NO 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 Mixture NO 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 Mixture NO 800 ppm in Nitrogen (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 (± 0.05).
The Mixture NO 800 ppm in Nitrogen 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. Mixture NO 800 ppm in Nitrogen 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).
Training in administration
The key elements that need to be covered in training hospital personnel are as follows.
Correct set-up and connections
- Connections to the gas cylinder and to the ventilator patient breathing circuit Operation - Pre-use check list procedure (a series of steps required immediately prior to each patient initiation to ensure that the system is working properly and that the system is purged of NO2) - Setting the device for the correct concentration of nitric oxide to be administered - Setting the NO, NO2 and O2 monitors for high and low alarm limits
- Using the manual backup delivery system
- Procedures for correctly switching gas cylinders and purging system - Troubleshooting alarms
- NO, NO2 and O2 monitor calibration
- Monthly system performance check-up procedures

Monitoring formation of methaemoglobin (MetHb)
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 Mixture NO 800 ppm in Nitrogen therapy, using an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is > 2.5 %, the Mixture NO 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 Mixture NO therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the Mixture NO dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered.

Monitoring formation of nitrogen dioxide (NO2)
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 Mixture NO 800 ppm in Nitrogen and/or FiO2 should be reduced if possible. If there is an unexpected change in Mixture NO concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated.