Source: Health Products and Food Branch (CA) Revision Year: 2016
KINOX (nitric oxide), in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and late pre-term (≥34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.
The safety and effectiveness of nitric oxide have been established in a population receiving other therapies for hypoxic respiratory failure, including vasodilators, intravenous fluids, bicarbonate therapy, and mechanical ventilation.
In clinical trials, no efficacy has been demonstrated with the use of nitric oxide in patients with congenital diaphragmatic hernia.
An adequate pharmacovigilance study, over a minimum of 5 years, will be carried out to confirm the long-term effects associated with the use of inhaled nitric oxide in neonates.
The minimum effective dose for the indication has not been optimally identified in randomized clinical trials. The initial dose of nitric oxide should be as low as possible and in no cases higher than 20 ppm for no more than 4 hours. In cases of failure to respond to nitric oxide at 4-6 hours after starting therapy, further steps should be considered. Between 4-24 hours attempts should be made to decrease the dose as quickly as possible to 5 ppm. Treatment with aggressive attempts to lower the dose to 5 ppm, should be maintained until underlying oxygen saturation has resolved but for no more than 96 hours of therapy at which time the neonate should be weaned from nitric oxide therapy. See Precautions: General section.
Efficacy and safety of nitric oxide have not been established beyond 96 hours of use. The duration of therapy is variable, but typically less than four days.
An initial dose of 20 ppm was used in the NINOS and CINRGI trials. In CINRGI, patients whose oxygenation improved with 20 ppm were dose-reduced to 5 ppm as tolerated at the end of 4 hours of treatment. In the NINOS trial, patients whose oxygenation failed to improve on 20 ppm could be increased to 80 ppm, but those patients did not then increase their PaO2 on the higher dose. The risk of methemoglobinemia and elevated NO2 levels increases significantly when nitric oxide is administered at doses >20 ppm.
The nitric oxide dose should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and elevation in PAP may also occur in neonates with no apparent response to nitric oxide.
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. 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.
When the decision is made to discontinue nitric oxide therapy, the dose should be lowered and steps taken to minimize the frequently encountered transient drop in PaO2 noted for 10 to 60 minutes after discontinuation of nitric oxide. One regimen that accomplished this is to reduce the dose to 1 ppm for 30 to 60 minutes. 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 hypoxemia. 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.
Healthcare professionals involved in the care of patients on nitric oxide therapy need to be trained by the manufacturer of the nitric oxide delivery system or have support from personnel trained by the manufacturer in the following key elements of nitric oxide delivery:
Prescription and administration of nitric oxide should be supervised by a physician experienced in neonatal intensive care. Prescription and administration 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 is delivered to the patient via mechanical ventilation after dilution with an oxygen/air mixture using an approved nitric oxide delivery system. 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 monitoring equipment. For patient safety, appropriate alerts must be set for nitric oxide (± 2 ppm of the prescribed dose), NO2 (0.5 ppm), and FiO2 (± 0.05). The nitric oxide cylinder pressure must be displayed to allow timely cylinder replacement without inadvertent loss of therapy and backup 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 availability of these backups will minimize the risk of loss of nitric oxide therapy resulting from failure of the primary nitric oxide administration apparatus. The power supply for the monitoring equipment should be independent of the delivery device function.
In order to minimize the risks of hypoxemia associated with acute interruption of drug therapy and accidental exposure, the device should include provision for attachment of two nitric oxide cylinders which can be used alternately via a manifold, or other means to assure a continuous supply of nitric oxide for normal operation of a primary administration system during replacement of cylinders.
Nitric oxide should be administered with monitoring for PaO2, methemoglobin, and NO2.
Neonates are known to have diminished methemoglobin reductase activity compared to adults. Methemoglobin level should be measured within one hour after initiation of nitric oxide therapy using an analyzer, which can reliably distinguish between fetal hemoglobin and methemoglobin. Although it is unusual for the methemoglobin level to increase significantly if the first level is low, it is prudent to repeat methemoglobin measurements periodically throughout the treatment period. If methemoglobin is >2.5%, the nitric oxide dose should be decreased and the administration of reducing agents such as methylene blue may be considered.
Immediately prior to each patient initiation, proper procedure must be applied to purge the nitric oxide delivery 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 analyzer 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 analyzer should be recalibrated.
Overdosage with nitric oxide will be manifest by elevations in methemoglobin and NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobinemia reduce the oxygen delivery capacity of the circulation.
Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.
For management of a suspected drug overdose, contact your regional Poison Control Centre
The shelf life of KINOX is 24 months. Store cylinders between 15-30ºC (59-86ºF).
All regulations concerning handling of pressure vessels must be followed.
Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition.
The installation of a nitric oxide pipeline system with supply station of cylinders, fixed network and terminal units substantially increases the risk of NO2 formation and delivery to patients and is strongly discouraged.
Transport of cylinders: The cylinders should be transported with appropriate material in order to protect them from risks of shocks and falls.
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