Index of drugs

Including breathing assistance and other relevant active substances: in the treatment of newborns born ≥34 weeks of pregnancy with hypoxic respiratory failure associated with clinically or echocardiographically confirmed pulmonary hypertension, to improve oxygenation and minimize the need for extracorporeal gas exchange (ECMO); as an element of perioperative and post-operative pulmonary hypertension in adults and newborns, infants and young children, children and adolescents from 0 to 17 years combined with heart surgery, to selectively reduce pulmonary artery pressure and improve the function of the right ventricle and blood oxygenation.

Nitric oxide (NO) 800 ppm (V / V) in nitrogen. From gas cylinders filled under an absolute pressure of 200 bar, we obtain: from a two-liter gas cylinder - 381 l of gas at a pressure of 1 bar at 15 ° C; from a 10-liter gas cylinder - 1535 l of gas at a pressure of 1 bar at 15 ° C.

Pulmonary gas expanding gas. Nitric oxide increases the arterial pressure of arterial oxygen probably by expanding the pulmonary vasculature in better ventilated areas of the lungs, thereby moving the blood flow from areas of low ventilation to perfusion (V / Q) to areas with normal V / Q. After inhalation, it is absorbed into the bloodstream, the greater part penetrates through the capillaries in the lungs, where it binds with oxyhemoglobin. It can also be associated with oxygen and water or in the case of low oxygen saturation with deoxyhemoglobin. The final products of nitric oxide transformations that get into the systemic circulation are methemoglobin and nitrate. Nitrate accounts for> 70% of inhaled dose of nitric oxide, and is excreted in the urine.

Hypersensitivity to the active substance or to any of the excipients. Patients with congenital or acquired deficiency of methemoglobin reductase or glucose-6-phosphate dehydrogenase. Newborn children with left-right leak or significant left-right blood leak. 

If the clinical response is considered unsuitable after 4-6 h from the start of treatment, the issues described below should be considered. For patients transferred to another hospital, nitric oxide should be available during transport to prevent deterioration due to abrupt discontinuation. In case of permanent deterioration of the patient or lack of improvement (in accordance with the on-site criteria), consideration should be given to the use of emergency measures, such as extracorporeal membrane oxygenation (ECMO) (if available). Clinical studies have not demonstrated the efficacy of using inhaled nitric oxide in patients with congenital diaphragmatic hernia. Treatment with inhaled nitric oxide may exacerbate heart failure in the case of left-right leakage. It is associated with unwanted vasodilation in the lung through inhaled nitric oxide, resulting in a further increase in existing pulmonary hyperperfusion. This may result in failure or retrograde failure. It is therefore recommended that pulmonary artery catheterization or echocardiography be performed prior to nitric oxide administration to determine haemodynamic parameters. Caution should be exercised when using inhaled nitric oxide in patients with complex heart defects, in whom high pulmonary artery pressure is important for the stability of cardiovascular parameters. Caution should also be exercised in patients with impaired left ventricular function and at baseline elevated congestion pressure (PCWP), as they may be more at risk of developing heart failure (such as pulmonary edema). Treatment with the preparation should not be discontinued suddenly, as it may lead to an increase in pressure in the pulmonary arteries and / or deterioration of blood oxygenation (PaO₂).Deterioration of oxygenation of blood and increase in pressure in pulmonary arteries may also occur in newborn children who do not respond to the preparation. Discontinue preparation with caution. In the case of patients transferred to other facilities in connection with additional treatment, in which continued treatment is necessary, treatment should be provided during transport. The doctor should have access to a spare inhalation kit for administering nitric oxide at the patient's bedside. The main end products of nitric oxide metabolism that appear in the peripheral circulation are methemoglobin and nitrate. Methemoglobin concentration in the blood should be monitored. Nitrogen dioxide is formed in a short time in gas mixtures containing nitric oxide and oxygen. Nitric oxide can thus cause inflammation and damage in the airways. If the concentration of NO₂ exceeds 0.5 ppm, the dose of nitric oxide should be reduced. Regular monitoring of haemostasis and clotting time is recommended during administration of the preparation for more than 24 hours in patients with platelet dysfunction or abnormalities, low coagulation factor levels and in patients receiving anticoagulant therapy.

Do not use during pregnancy or breastfeeding.

Very common: thrombocytopenia. Common: hypotension, atelectasis. Uncommon: methaemoglobinaemia. Frequency unknown: headache and dizziness, bradycardia (after abrupt cessation of treatment), hypoxia, dyspnoea, chest discomfort, dry mucous pharynx. Rapid rebound reactions such as increased pulmonary vasoconstriction and hypoxia have been reported following abrupt cessation of treatment leading to cardiovascular collapse. Abrupt discontinuation may lead to relapse, reduced oxygenation, and increased central pressure and further reduction of systemic blood pressure. Recurrence is the most common adverse reaction associated with the clinical use of inhaled nitric oxide. Recurrence may occur at the beginning as well as at the end of the treatment period.

Persistent pulmonary hypertension in newborns (PPHN). Treatment should only be carried out in neonatal units under the supervision of an experienced neonatologist. The preparation should be used in newborns whose estimated duration of mechanical ventilation will exceed 24 h. Use only after optimization of respiratory support - optimization of tidal volume / respiratory pressure and recruitment of alveoli (surfactant, high-frequency ventilation and positive pressure in the final phase of exhalation). The maximum recommended dose is 20 ppm. In clinical trials, the starting dose was 20 ppm. Starting as early as possible, during the first 4-24 hours of treatment, the dose should be gradually reduced to 5 ppm, provided that if a lower dose is used, arterial oxygenation is appropriate. Treatment with inhaled nitric oxide should be continued with a dose of 5 ppm, to achieve an improvement in oxygenation in the newborn, that FiO₂ (oxygen concentration in the breathing mixture) will be <0.60. Treatment can be continued up to 96 hours or until the cause causing hypoxia is removed and the newborn child is ready to stop treatment using nitric oxide. The duration of treatment may vary, but usually lasts less than 4 days. If there is no response to treatment with inhaled nitric oxide, see precautions.Discontinuation of the drug. Attempts to discontinue the preparation should be made after significant reduction of respiratory function support or after 96 hours of treatment. The dose should be reduced to 1 ppm for a period of 30 minutes to 1 hour. If the oxygenation does not change when the preparation is used in a dose of 1 ppm, FiO should be increased₂ by 10% and discontinue the preparation. Continue to closely monitor the respiratory parameters of the newborn in order to eliminate the symptoms of hypoxia. If the oxygenation decreases by> 20%, the administration should be resumed at a dose of 5 ppm. Discontinuation should be considered again after a 12-24 h period. Children who are unable to discontinue the treatment after 4 days should be subjected to detailed diagnostic tests to detect other conditions.Pulmonary hypertension associated with heart surgery. Treatment should be under the supervision of a physician with relevant experience in the field of anesthesiology and intensive care of patients after cardiac or surgical procedures, only in cardiotorax surgery departments. The preparation should only be used after optimization of conservative treatment. In clinical trials, nitric oxide was used as an adjunct to standard treatments in perioperative conditions, including the use of inotropic and vasoactive drugs. The preparation should be administered with close observation of hemodynamics and blood oxygenation.newbornsinfants and young children, children and adolescents (from 0 to 17 years). The initial dose is 10 ppm. It can be increased to 20 ppm if the lower dose did not allow to achieve sufficient clinical effects. The lowest effective dose should be administered and should be reduced to 5 ppm provided the pulmonary artery pressure and arterial oxygenation remain normal. There are limited clinical data justifying the use of the suggested dose in children from 12 to 17 years of age. The safety and efficacy of the preparation in premature babies born before 34 weeks of gestation have not been established.Adults. The starting dose is 20 ppm. The dose can be increased to 40 ppm if the initial dose has not produced sufficient clinical effect. The lowest effective dose should be administered and then it should be reduced to 5 ppm, provided that normal pulmonary artery pressure and normal arterial oxygenation are maintained. The reduction of pulmonary artery pressure and improvement of oxygenation take place within 5-20 min. If the effect is insufficient, the dose can be increased at the earliest after 10 min. Discontinuation of the preparation should be considered if there are no beneficial physiological effects after 30 min. Treatment can be started at any time during the perioperative period to lower the pulmonary pressure. In clinical trials, treatment was often started before disconnecting the extracorporeal circulation. Nitric oxide was administered by inhalation for up to 7 days in perioperative conditions, but usually the duration of treatment was 24-48 h.Discontinuation of the drug. Attempts to discontinue the preparation should be made immediately after haemodynamic stabilization, with simultaneous change of mechanical ventilation parameters and reduction of doses of inotropic drugs. Dose gradually reduce to 1 ppm for 30 min, with close observation of peripheral and central pressure, then the preparation should be discontinued. If the patient's condition is stable at a low dose, withdrawal attempts should be repeated at least every 12 hours.Method of administration. Endotracheal and bronchial administration. Nitric oxide is administered by mechanical ventilation after dilution with a mixture of oxygen and air, using the inhalation kit for nitric oxide. The inhalation kit must provide a constant concentration of the inhaled drug, regardless of the mechanical ventilation settings made in the ventilator. When using a fixed-pressure neonatal respirator, this can be achieved by introducing low-flow nitrous oxide to the respiratory part of the ventilator system. Intravenous ventilation used in newborns may be associated with rapid jumps in the concentration of nitric oxide. A set for feeding nitric oxide at intermittent ventilation should be constructed in such a way as to prevent sudden changes in the concentration of nitric oxide. The concentration of inhaled nitric oxide must be measured continuously in the ventilator's respiratory system, a short distance from the patient's body. At the same point, the measurement of the concentration of nitrogen dioxide (NO₂) and FiO₂. For reasons of patient safety, the alarm system should be set (± 2 ppm from the recommended dose), NO₂ (1 ppm) and FiO₂ (±0,05). Monitoring the formation of methemoglobin (MetHb). Measurement of MetHb concentration should be carried out within 1 h of the start of nitric oxide therapy, using an analyzer that can effectively distinguish MetHb from fetal hemoglobin. If the MetHb concentration is> 2.5%, the dose of nitric oxide should be reduced and the use of reducing agents such as methylene blue should be considered. In adults undergoing heart surgery, measurement of MetHb concentration should be performed within one hour of starting treatment with nitric oxide using Messer's nitrous oxide.If the MetHb fraction rises to a level that has the potential to adversely affect the proper oxygen distribution, the nitric oxide dose should be changed and the use of reducing agents such as methylene blue should be considered. In newborns and infants, it is recommended to measure MetHb concentration daily or every 2 days.Monitoring of the formation of nitrogen dioxide (NO₂). NO concentration₂ should be kept as low as possible, not higher than 0.5 ppm. If the concentration of NO₂ will be greater than 0.5 ppm, check that the installation is working properly, recalibrate the NO analyzer₂, and if possible reduce the dose of nitric oxide and / or FiO₂. If the nitric oxide concentration changes unexpectedly, check that the delivery system is working properly and recalibrate the analyzer.