Abstract:
The invention concerns a gaseous medicine comprising a mixture of nitrogen monoxide (NO) and nitrogen (N2) for use by inhalation for the treatment of hypoxemic respiratory failure linked to pulmonary vasoconstriction in humans, said gaseous mixture containing between 1200 and 4500 ppm by volume (ppmv) of nitrogen monoxide (NO) and said hypoxemic respiratory failure being chosen from acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension of the newborn infant (PPHN).

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a 371 of International Application PCT/FR2013/050817 filed Apr. 15, 2013, which claims priority to French Application No. 1254765 filed May 24, 2012, the entire contents of which are incorporated herein by reference. 
     
    
     BACKGROUND 
       [0002]    The invention relates to a gaseous medicament based on nitrogen monoxide (NO) and between 1200 and 4500 ppm by volume of nitrogen monoxide (NO), used by inhalation for treating hypoxemic respiratory distress linked to pulmonary vasoconstriction in humans, such as ARDS or persistent pulmonary hypertension of the newborn (PPHN). 
         [0003]    Hypoxemia is the medical term used for describing the decrease in the amount of oxygen contained in the blood. Hypoxemia may be the result of certain respiratory pathologies, such as acute respiratory distress syndrome (ARDS) or primary pulmonary hypertension of the newborn (PPHN). 
         [0004]    ARDS is a critical condition that is life-threatening for the person who is suffering therefrom, in which the pulmonary compliance and the capacity for gas exchanges drop radically, which results in a deterioration of the alveolar-capillary membrane leading to a pulmonary edema. 
         [0005]    The most commonly used definition of ARDS is the one from the following document:  The American - European Consensus Conference on ARDS, Am J Respir Crit Care Med.  1994 March; 149 (3 Pt 1): 818-24. According to this document, ARDS is characterized by:
       a clinical condition of the patient with respiratory distress of acute onset,   disturbed blood gases with PaO 2 /FiO 2  ratio&lt;200,   bilateral infiltrate on lung radiograph,   non-cardiogenic pulmonary edema (PAOP≦18 mm Hg), and   good echocardiographic function or no clinical signs of heart failure.       
 
         [0011]    Furthermore, PPHN is a form of pulmonary hypertension observed in newborns, the cause of which is a persistence of pulmonary artery vasospasm after birth. In fact, during pregnancy, the lungs of the fetus are not used for gas exchanges, i.e. intake of oxygen and removal of CO 2 , and fetal circulation sends most of the blood far from the lungs owing to special connections in the heart and the large blood vessels. 
       SUMMARY 
       [0012]    At birth, the newborn begins to breathe air. The change in pressure in the lungs that results therefrom then normally helps to make good the connections of the newborn and to redirect the blood flow, that is to say that the blood is pumped to the lungs in order to help with the gas exchanges. However, when the newborn has a low level of oxygen or respiratory difficulties at birth, these changes may not occur and the blood circulation continues to take place as before the birth, that is to say that the blood is directed far from the lungs but, in this case, the pressure of the lungs remains high. 
         [0013]    If the blood is sent far from the lungs, the latter cannot carry out the gas exchanges, that is to say the capture of oxygen and the removal of carbon dioxide, even if the newborn is supplied with 100% by volume of oxygen. 
         [0014]    Babies suffering from PPHN therefore have low blood oxygen levels, which may be dramatic insofar as all the organs of the body depend on oxygen-rich blood and, hence, in the case of insufficient blood perfusion, they may be damaged by lack of oxygen. 
         [0015]    In both cases, the patient suffers hypoxemic respiratory distress linked to a pulmonary vasoconstriction, that is to say a vasoconstriction of the blood vessels of the lungs leading to impaired pulmonary gas exchanges and a poor blood supply of the lungs. 
         [0016]    Currently, one treatment known for treating pathologies of this type consists of an administration, by inhalation, of NO gas to the patient. 
         [0017]    Thus, Kinox™ is a gaseous medicament formed from a mixture of NO (225 or 450 ppm by volume) and nitrogen indicated, in combination with assisted ventilation and conventional treatment, in the treatment of newborns having a gestational age of at least 34 weeks exhibiting hypoxemic respiratory distress combined with clinical or echocardiographic signs of pulmonary arterial hypertension, with the purpose of improving oxygenation and avoiding recourse to extracorporeal oxygenation. The dosage is determined by the clinical condition of the patient but the maximum recommended dose is 20 ppm by volume. 
         [0018]    Furthermore, documents EP-560928, EP-A-1516639 and EP-A-786264 recommend using NO/N 2  gas mixtures that contain up to 800 ppm by volume of NO. 
         [0019]    Just before it is administered, the NO/N 2  mixture is diluted with a gas containing at least 21% oxygen, such as air, O 2 -enriched air or an N 2 /O 2  mixture, so as to make the mixture thus obtained non-hypoxic. This dilution makes it possible to decrease the concentration of NO in the gas administered to less than 40 ppmv, i.e. to the dosage desired for the patient in question. This is generally carried out in the patient circuit of a ventilator. 
         [0020]    However, in order to minimize the formation of toxic NO 2  by reaction of NO with oxygen, the mixture obtained containing NO and oxygen cannot be stored for long time and must be administered immediately after having been mixed. This is conventionally carried out in the ventilation circuit of a ventilation device, that is to say a respirator. 
         [0021]    It follows therefrom that with the known NO/N 2  mixtures containing 225, 450 or 800 ppmv, mixing with air or an oxygen-rich gas leads not only to a dilution of the NO but also inevitably of the oxygen which will lead to a reduction in the concentration of O 2  in the mixture administered to the patient. 
         [0022]    By way of example, an NO/N 2  mixture containing 800 ppmv of NO mixed with air (O 2  content of 21% by vol.) that must be administered by inhalation to a patient at a final concentration of 40 ppmv of NO, will have to undergo a 20-times dilution, namely 1 volume of NO/N 2  per 19 volumes of air. The air will then also undergo a dilution (dilution factor of 19/20) and the final O 2  content will be less than 20%, therefore less than the content in the ambient air. 
         [0023]    Yet patients suffering from hypoxemic respiratory distress already have an insufficient blood oxygen content. 
         [0024]    Hence, it is understood that the dilution of the oxygen with the NO/N 2  mixture may be problematic for the patient. 
         [0025]    In view of this, the problem that is addressed is to propose an inhalable gaseous medicament based on NO for which the dilution effect will be lower than with the existing mixtures. 
         [0026]    In other words, the present invention aims not to lower the FiO 2  provided to the patient due to a great dilution of the oxygen with the gas containing the NO, while guaranteeing an effective treatment of the vasoconstrictions linked to hypoxemiac respiratory distresses of PPHN, ARDS or other type. 
         [0027]    The solution of the invention is then a gaseous medicament comprising a mixture of nitrogen monoxide (NO) and nitrogen (N 2 ) for use by inhalation for treating hypoxemic respiratory distress linked to a pulmonary vasoconstriction in humans, said gas mixture containing between 1200 and 4500 ppm by volume (ppmv) of nitrogen monoxide (NO) and said hypoxemic respiratory distress being selected from acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension of the newborn (PPHN). 
         [0028]    Depending on the case, the medicament of the invention may comprise one or more of the following technical features:
       the NO/N 2  mixture is mixed, before the inhalation thereof, with an additional gas containing at least 21% by volume of oxygen.   the additional gas contains at least 25% by volume of oxygen.   the additional gas contains at least 30% by volume of oxygen.   the additional gas contains at least 40% by volume of oxygen.   the additional gas contains at least 50% by volume of oxygen.   the additional gas contains at least 60% by volume of oxygen.   the additional gas contains at least 70% by volume of oxygen.   the additional gas contains at least 80% by volume of oxygen.   the additional gas contains from 90% to 100% by volume of oxygen.   the additional gas is selected from oxygen, air, air/oxygen mixtures, that is to say air to which oxygen or an oxygen-containing gas has been added, or nitrogen/oxygen mixtures.   the NO/N 2  gas mixture contains at least 1300 ppmv of NO, preferably at least 1400 ppmv of NO, and nitrogen (N 2 ) for the remainder.   the NO/N 2  gas mixture contains at least 1500 ppmv of NO and nitrogen (N 2 ) for the remainder.   the NO/N 2  gas mixture contains less than 3500 ppmv of NO.   the NO/N 2  gas mixture contains between 1500 and 4500 ppmv of NO.   the NO/N 2  gas mixture contains from 1500 to 2500 ppmv of NO.   the NO/N 2  gas mixture is contained in a container having an internal volume of less than or equal to 12 liters (water equivalent).   the container containing the NO/N 2  gas mixture is of cylindrical shape and comprises, at one end, a base and, at the other end, a neck with an outlet orifice, attached to which is a device for controlling the gas flow and/or for reducing the pressure.   the NO/N 2  gas mixture is contained in a gas cylinder.   the container containing the NO/N 2  gas mixture comprises a neck with an outlet orifice, attached to which is an integrated valve regulator.   the NO/N 2  gas mixture is stored in a container at a pressure of from 100 to 500 bar absolute, preferably between 140 and 350 bar absolute.   the NO/N 2  gas mixture is stored in a container equipped with a valve or an integrated valve regulator.   the NO/N 2  gas mixture is stored in a container of cylindrical shape having a diameter between 5 and 40 cm and a height between 10 and 80 cm.   the human treated is an adult, child or a newborn.   the NO/N 2  gas mixture is diluted with an oxygen-containing gas in a ventilation circuit of a respirator or a medical ventilator.   the NO/N 2  gas mixture is delivered continuously into the ventilation circuit of the respirator.   alternatively, the NO/N 2  gas mixture is delivered in a pulsed manner into the ventilation circuit of the respirator.       
 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
         [0055]    The present invention will now be better understood owing to the description given below with reference to the appended FIGURE. 
           [0056]      FIG. 1  represents one embodiment of an installation for dispensing NO that can be used within the context of the present invention. 
       
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0057]    Seen therein is an installation for dispensing NO that can be used to administer a gaseous mixture of NO and nitrogen at high concentration, that is to say 1200 ppm or more, preferably between 1500 and 4500 ppm, to a patient P with hypoxemic respiratory distress with an FiO 2  of around 100%, for example an adult suffering from ARDS or a newborn suffering from persistent pulmonary hypertension. 
         [0058]    This installation comprises a ventilator  1  comprising a respiratory circuit or patient circuit  2  with two branches, that is to say with an inhalation branch  3  and an exhalation branch  4 . The inhalation branch  3  is designed to convey respiratory gas from the ventilator  1  to the patient P, whereas the exhalation branch  4  is designed to convey the gas exhaled by the patient P to the ventilator  1 . 
         [0059]    At the patient P, the gas is administered by means of a patient interface  11 , for example a respiratory mask or a tracheal cannula or catheter. 
         [0060]    The ventilator  1  is supplied, via a first delivery line  10 , with air (O 2  content of 21% by volume) originating from an air source  7  and via a second delivery line  10 ′ with oxygen resulting from an oxygen source  7 ′, such as an oxygen cylinder or a duct transporting oxygen originating from an oxygen production unit, such as a pressure swing (PSA) unit, or from an oxygen storage unit, such as a buffer or storage tank. 
         [0061]    The oxygen-rich gas is delivered by the ventilator  1  into the inhalation branch  3  of the patient circuit  2 . 
         [0062]    Furthermore, a device  5  for dispensing NO is fluidically connected to said inhalation branch  3  of the patient circuit  2  in order to deliver therein, via a feed line  12 , an NO/N 2  mixture containing a high concentration of NO, that is to say at least 1200 ppm by volume, according to the present invention. 
         [0063]    The device  5  for dispensing NO is itself supplied with an NO/N 2  mixture, via a gas feed line  9 , by a source of NO  6  such as a gas cylinder equipped with a valve or integrated valve regulator  8 , preferably protected by a cap for protection against impacts. 
         [0064]    The device  5  for dispensing NO makes it possible in particular to control the amount of NO/N 2  released into the inhalation branch  3 , and also the method of releasing this mixture, that is to say continuously or in a pulsed manner, for example only during the inhalation phases of the patient P. 
         [0065]    Therefore, in the inhalation branch  3 , a dilution of the NO/N 2  mixture with the oxygen-rich gas dispensed by the ventilator  1  takes place. 
         [0066]    The dilution depends on the content of the initial NO/N 2  mixture but also on the concentration of gas to be administered to the patient. 
         [0067]    The NO/N 2  gas mixture according to the invention is therefore an inhalable medicament that can be used in combination with an assisted ventilation  1  for the treatment in particular of newborns having a gestational age of at least 34 weeks exhibiting hypoxemic respiratory distress combined with clinical or echocardiographic signs of pulmonary arterial hypertension, with the purpose of improving oxygenation and avoiding recourse to extracorporeal oxygenation. 
         [0068]    It may also be used for treating adults or children suffering from ARDS. 
         [0069]    The examples below give examples of mixtures that can be used in patients suffering from ARDS or PPHN. 
       Example 1 
     Adult Suffering from ARDS 
       [0070]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                 Comparative 
               
               
                   
                   
                 Invention 
                 (prior art) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 NO content of the initial 
                 2000 
                 ppmv 
                 450 
                 ppmv 
               
               
                   
                 NO/N 2  mixture 
               
               
                   
                 Ventilation 
                 10 
                 l/min 
                 10 
                 l/min 
               
             
          
           
               
                   
                 Ventilator set point FiO 2   
                 60% 
                   60% 
               
             
          
           
               
                   
                 Final content to be 
                 20 
                 ppmv 
                 20 
                 ppmv 
               
               
                   
                 administered to the patient 
               
             
          
           
               
                   
                 Dilution factor 
                  1% 
                  4.5% 
               
               
                   
                 Actual FiO 2  after dilution 
                 59% 
                 55.4% 
               
               
                   
                   
               
             
          
         
       
     
       Example 2 
     Newborn Suffering from PPHN 
       [0071]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Comparative 
                 Comparative 
               
               
                   
                 Invention 
                 (prior art) 
                 (prior art) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 NO content of the initial 
                 2000 
                 ppmv 
                 450 
                 ppmv 
                 225 
                 ppmv 
               
               
                 NO/N 2  mixture 
               
               
                 Ventilation 
                 2 
                 l/min 
                 2 
                 l/min 
                 2 
                 l/min 
               
             
          
           
               
                 Ventilator set point FiO 2   
                 100% 
                 100% 
                 100% 
               
             
          
           
               
                 Final content to be 
                 20 
                 ppmv 
                 20 
                 ppmv 
                 20 
                 ppmv 
               
               
                 administered to the patient 
               
             
          
           
               
                 Dilution factor 
                  1% 
                  4.5% 
                 9.08%  
               
               
                 Actual FiO 2  after dilution 
                 98.2%  
                 92.3%  
                  85% 
               
               
                   
               
             
          
         
       
     
         [0072]    Seen in tables 1 and 2 is the advantage of using high concentrations of NO in the initial mixture, all the more so when the target dosages of NO are high (e.g. non-responsive patient requiring dosages of greater than 20 ppmv) and when the required FiO 2  values are also high, that is to say of the order of 90% to 100%. 
         [0073]    Indeed, such high FiO 2  values cannot be maintained for excessively low initial concentrations, that is to say of less than 1000 ppmv approximately, and in this case, the positive effects of the NO are offset by the deleterious effects of the dilution on the FiO 2 . 
         [0074]    Generally, the invention also relates to a therapeutic treatment method, wherein a gaseous medicament comprising a mixture of nitrogen monoxide (NO) and nitrogen (N 2 ) is administered by inhalation to a patient suffering from hypoxemic respiratory distress linked to pulmonary vasoconstriction, such as ARDS, or PPHN, said gas mixture containing at least 1200 ppm by volume (ppmv) of nitrogen monoxide (NO), and said patient being an adult, a child or a newborn. 
         [0075]    Prior to being administered to the patient, the mixture of nitrogen monoxide (NO) and nitrogen (N 2 ) is diluted with an oxygen-containing gas, preferably this dilution is carried out in the ventilation circuit of a medical ventilator or the like. 
         [0076]    Generally, table 1 below shows the volumes (in ml) of NO/N 2  administered in the inhalation branch  3  of the patient circuit  2  of the ventilator  1  for a volume per minute of 10 l/min of the ventilator (i.e. air/O 2 ), in order to obtain NO concentrations between 5 and 40 ppmv, as a function of the NO concentration in the cylinder containing the NO/N 2  mixture, i.e. ranging from 100 to 3500 ppmv. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
             
             
               
                   
                   
               
               
                   
                 NO concentration in the cylinder (ppmv) 
               
             
          
           
               
                 NO final dose 
                 100 
                 200 
                 225 
                 400 
                 450 
                 800 
                 1000 
                 1500 
                 2000 
                 2250 
                 2700 
                 3500 
               
               
                   
               
             
          
           
               
                  5 ppmv 
                 556 
                 256 
                 227 
                 127 
                 112 
                 63 
                 50 
                 33 
                 25 
                 22 
                 19 
                 14 
               
               
                 10 ppmv 
                 1111 
                 513 
                 455 
                 253 
                 225 
                 126 
                 101 
                 67 
                 50 
                 45 
                 37 
                 29 
               
               
                 20 ppmv 
                 2222 
                 1026 
                 909 
                 506 
                 449 
                 252 
                 201 
                 134 
                 100 
                 89 
                 74 
                 57 
               
               
                 40 ppmv 
                 4444 
                 2051 
                 1818 
                 1013 
                 899 
                 503 
                 402 
                 268 
                 201 
                 178 
                 148 
                 114 
               
               
                   
               
             
          
         
       
     
         [0077]    As can be seen in table 1, the volumes of NO administered in order to obtain doses of 5 ppmv are respectively 556 ml for a concentration of 100 ppmv of NO and 14 ml for a concentration of 3500 ppmv. Likewise, for doses of 40 ppmv, the volumes are 4444 ml for a concentration of 100 ppmv of NO and 114 ml for an NO concentration of 3500 ppmv. 
         [0078]    This clearly demonstrates the advantage that there is in using high NO concentrations, that is to say of at least 1200 ppmv, in order to reduce the impact of the volume of NO administered and of the associated dilution on the ventilator parameters (see table 2) since the higher the concentration, the lower the volume of NO required. 
         [0079]    Furthermore, table 2 illustrates the dilution percentages (%) obtained for NO concentrations from 100 to 3500 ppmv in order to obtain doses ranging from 5 to 40 ppmv, under the same administration conditions as those from table 1 (i.e. ventilation of 10 l/min). 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 2 
               
               
                   
                   
               
             
             
               
                   
                 NO concentration in the cylinder (ppmv) 
               
             
          
           
               
                 NO final dose 
                 100 
                 200 
                 225 
                 400 
                 450 
                 800 
               
               
                   
               
               
                  5 ppmv 
                 5.56% 
                 2.56% 
                 2.27% 
                 1.27% 
                 1.12% 
                 0.63% 
               
               
                 10 ppmv 
                 11.11% 
                 5.13% 
                 4.55% 
                 2.53% 
                 2.25% 
                 1.26% 
               
               
                 20 ppmv 
                 22.22% 
                 10.26% 
                 9.09% 
                 5.06% 
                 4.49% 
                 2.52% 
               
               
                 40 ppmv 
                 44.44% 
                 20.51% 
                 18.18% 
                 10.13% 
                 8.99% 
                 5.03% 
               
               
                   
               
             
          
           
               
                 1000 
                 1500 
                 2000 
                 2250 
                 2700 
                 3500 
               
               
                   
               
               
                 0.50% 
                 0.33% 
                 0.25% 
                 0.22% 
                 0.19% 
                 0.14% 
               
               
                 1.01% 
                 0.67% 
                 0.50% 
                 0.45% 
                 0.37% 
                 0.29% 
               
               
                 2.01% 
                 1.34% 
                 1.00% 
                 0.89% 
                 0.74% 
                 0.57% 
               
               
                 4.02% 
                 2.68% 
                 2.01% 
                 1.78% 
                 1.48% 
                 1.14% 
               
               
                   
               
             
          
         
       
     
         [0080]    As can be seen, for a same treatment set point, the dilution becomes negligible for high NO concentrations, that is to say of at least 1200 ppmv, and hence no longer influences the ventilator parameters and set points. Indeed, the lower the volume of NO, the less it will change the ventilation set points and counteract the beneficial effects of the treatment, in particular the FiO 2 . 
         [0081]    According to the invention, the use of a gas mixture containing at least 1200 ppm by volume (ppmv) of nitrogen monoxide (NO), typically containing from 1200 to 4500 ppmv, is therefore recommended. 
         [0082]    Lastly, tables 3 to 5 below show the impact of the dilutions on the desired FiO 2  values for initial NO concentrations in the cylinder of 225, 450 and 2000 ppmv. 
         [0083]    The FiO 2  is a very important parameter within the context of the illnesses treated by NO (neonatal refractory hypoxemia, ARDS, etc.) given that for these illnesses FiO 2  values of the order of 100% may be necessary. 
         [0084]    This implies that the dilution must be as low as possible in order to retain an FiO 2  value as high as possible and therefore the beneficial effect of the treatment by inhaled NO. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 3 
               
               
                   
                   
               
             
             
               
                   
                 FiO 2  desired (%) 
               
             
          
           
               
                     225 ppmv NO 
                 21 
                 23 
                 40 
                 60 
                 100 
               
             
          
           
               
                   
                 FiO 2  obtained (%) 
               
             
          
           
               
                  5 ppmv 
                 20.52 
                 22.48 
                 39.09 
                 60.00 
                 97.73 
               
               
                 10 ppmv 
                 19.59 
                 21.46 
                 37.31 
                 57.27 
                 93.29 
               
               
                 20 ppmv 
                 17.81 
                 19.51 
                 33.92 
                 52.07 
                 84.80 
               
               
                 40 ppmv 
                 14.57 
                 15.96 
                 27.75 
                 42.60 
                 69.39 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 4 
               
               
                   
                   
               
             
             
               
                   
                 FiO 2  desired (%) 
               
             
          
           
               
                     450 ppmv NO 
                 21 
                 23 
                 40 
                 60 
                 100 
               
             
          
           
               
                   
                 FiO 2  obtained (%) 
               
             
          
           
               
                  5 ppmv 
                 20.76 
                 22.74 
                 39.55 
                 59.33 
                 98.88 
               
               
                 10 ppmv 
                 20.30 
                 22.23 
                 38.66 
                 57.99 
                 96.65 
               
               
                 20 ppmv 
                 19.39 
                 21.23 
                 36.92 
                 55.39 
                 92.31 
               
               
                 40 ppmv 
                 17.64 
                 19.32 
                 33.61 
                 50.41 
                 84.01 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
               
                   
                   
               
             
             
               
                   
                 FiO 2  desired (%) 
               
             
          
           
               
                     2000 ppmv NO 
                 21 
                 23 
                 40 
                 60 
                 100 
               
             
          
           
               
                   
                 FiO 2  obtained (in %) 
               
             
          
           
               
                  5 ppmv 
                 20.95 
                 22.94 
                 39.90 
                 59.85 
                 99.749 
               
               
                 10 ppmv 
                 20.84 
                 22.83 
                 39.70 
                 59.55 
                 99.249 
               
               
                 20 ppmv 
                 20.63 
                 22.60 
                 39.30 
                 58.95 
                 98.254 
               
               
                 40 ppmv 
                 20.22 
                 22.15 
                 38.51 
                 57.77 
                 96.284 
               
               
                   
               
             
          
         
       
     
         [0085]    As can be seen in tables 3 and 4 relating to low initial contents of NO, namely 225 and 450 ppmv of NO (remainder nitrogen), the decreases of FiO 2  caused by the dilution may represent around 20% to 30% of the desired FiO 2  (i.e. the set point FiO 2 ), which becomes prejudicial to the treatment by NO since a low FiO 2  value cancels out the positive effects of the NO. 
         [0086]    Conversely, as shown in table 5, using a high concentration of NO (here 2000 ppm of NO in nitrogen) does not modify or else negligibly modifies (i.e. around &lt;1%) the FiO 2  set points thus making it possible to treat patients with O 2  contents of almost 100% over short periods, in order to get through certain extreme situations. 
         [0087]    Although an increase in the concentration of NO in the cylinders may appear simple at first glance, it does entail problems linked to the potential toxicity of high contents of NO (&gt;800 ppmv), since any excessive dose, due to a poor dilution for example, may result in a toxic dose being administered to the patient and since, furthermore, the higher the concentration of NO, the greater the risk of forming toxic compounds, such as toxic NO 2  that is formed by oxidation of NO in the presence of oxygen. 
         [0088]    In other words, the solution proposed by the invention goes against certain prejudices that exist in the field in question, which consider that the use of NO at high doses, that is to say greater than 1200 ppmv, is dangerous and not recommended. 
         [0089]    It will be understood that many additional changes in the details, materials, steps and arrangement of parts, which have been described herein in order to explain the nature of the invention, may be made by those skilled in the art within the principle and scope of the invention as expressed in the appended claims. Thus, the present invention is not intended to be limited to the specific embodiments in the examples given above.