EP2854766A1

EP2854766A1 - No/nitrogen gaseous mixture with a high no content for the treatment of severe hypoxemic respiratory failure

Info

Publication number: EP2854766A1
Application number: EP13744585.4A
Authority: EP
Inventors: Pierre de Villemeur; Laurent Lecourt
Original assignee: Air Liquide Sante International SA
Current assignee: Air Liquide Sante International SA
Priority date: 2012-05-24
Filing date: 2013-04-15
Publication date: 2015-04-08
Also published as: FR2990858B1; CA2874019A1; WO2013175088A1; US20150125552A1; FR2990858A1; CN104379126A; BR112014029296A2

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

NO / nitrogen gas mixture with a high NO content to treat distress

severe hypoxemic respiratory

A nitric oxide (NO) gaseous drug and between 1200 and 4500 ppm by volume of nitric oxide (NO), used by inhalation to treat hypoxemic respiratory distress related to pulmonary vasoconstriction in humans, such as ARDS or persistent pulmonary hypertension of the newborn (HPPN).

Hypoxemia is the medical term used to describe the decrease in the amount of oxygen in the blood. Hypoxemia may be the result of certain respiratory conditions, such as Acute Respiratory Distress Syndrome (ARDS) or Primary Neonatal Pulmonary Hypertension (HPPN).

ARDS is a critical condition that is life-threatening for the person affected, in which pulmonary compliance and gas exchange capacity drop dramatically, resulting in alveolar-capillary membrane involvement leading to pulmonary edema.

The most commonly used definition of ARDS is that of the following document: The American-European Consensus Conference on ARDS, Am J Respir Crit Care Med. 1994 Mar; 149 (3 Pt 1): 818-24. According to this document, an ARDS is characterized by:

- a clinical condition of the patient with acute respiratory distress,

disturbed blood gases with a Pa0 ₂ / Fi0 ₂ <200 ratio,

- a lung x-ray with bilateral infiltrate,

- no cardiac etiology at pulmonary edema (PAPO <18 mm Hg), and

- good cardiac function on ultrasound or no clinical signs of heart failure.

In addition, HPPN is a form of pulmonary hypertension observed in neonates whose cause is a persistence of vasospasm of the pulmonary arteries after birth. In fact, during pregnancy, the fetal lungs are not used for gas exchange, oxygen entry and CO ₂ release, and the fetal circulation sends most of the blood away from the lungs through special connections in the lungs. heart and large blood vessels.

At birth, the newborn begins to breathe air. The resulting change in pressure in the lungs then normally helps to bridge the neonate's connections and redirect blood flow, that is, blood is pumped to the lungs to aid gas exchange. However, when the newborn has a low oxygen level or breathing difficulties at birth, these changes do not occur. can occur and the blood flow continues to be as before birth, ie the blood is directed far into the lungs but in this case, the pressure of the lungs remains high.

However, if the blood is sent away from the lungs, they can not ensure the gas exchange, that is to say the capture of oxygen and the elimination of carbon dioxide, and this, even if the new -need is fed with 100% by volume of oxygen.

Babies with HPPN therefore have low blood oxygen levels, which can be dramatic as all of the body's organs are dependent on oxygen-rich blood and, therefore, if insufficient blood supply is available, they can be damaged by lack of oxygen.

In either case, the patient experiences hypoxemic respiratory distress related to pulmonary vasoconstriction, that is, vasoconstriction of the blood vessels of the lungs resulting in lung-deficient gas exchange and poor blood supply. lungs.

Currently, a known treatment to treat this type of diseases consists of an administration by inhalation of gaseous NO to the patient.

Thus, Kinox ™ is a gaseous drug consisting of a mixture of NO (225 or 450 ppm by volume) and nitrogen indicated in combination with assisted ventilation and conventional treatment for treatment of gestational age infants. at least 34 weeks, with hypoxemic respiratory distress associated with clinical or echocardiographic signs of pulmonary arterial hypertension, with the aim of improving oxygenation and avoiding the use of extracorporeal circulation oxygenation. The dosage is determined by the clinical condition of the patient but the maximum recommended dose is 20 ppm by volume.

Furthermore, the documents EP-560928, EP-A-1516639 and EP-A-786264 recommend the use of gaseous NO / N ₂ mixtures containing up to 800 ppm by volume of NO

Just prior to administration, the mixture NO / N ₂ was diluted with a gas containing at least 21% oxygen, such as air, air enriched with 0 ₂ or N _2/0 _2, so 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, that is to say up to the desired dosage for the patient in question. This is usually done in the patient circuit of a ventilator.

However, in order to minimize the formation of toxic NO ₂ by reacting NO with oxygen, the resulting mixture containing NO and oxygen can not be stored for long and must be administered immediately after mixing. This is conventionally done in the ventilatory circuit of a ventilation device, that is to say a respirator. It follows that with the known NO / N ₂ mixtures containing 225, 450 or 800 ppmv, the mixture with air or a gas rich in oxygen, not only causes a dilution of the NO but also inevitably of the oxygen which will cause a reduction in the concentration of 0 ₂ in the mixture administered to the patient.

For example, a NO / N ₂ mixture at 800 ppmv NO mixes with air (O ₂ content of 21% in vol.) To be administered by inhalation to a patient at a final concentration of 40 ppmv. in NO, will have to undergo a dilution of 20 times, ie 1 volume of NO / N ₂ for 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.

However, patients suffering from hypoxemic respiratory distress already have insufficient oxygen content in the blood.

Therefore, it is understood that the dilution of oxygen with the NO / N ₂ mixture can be problematic for the patient.

In view of this, the problem is to propose an inhalable gaseous drug based on NO for which the dilutive effect would be less than with existing mixtures.

In other words, the present invention aims not to lower F1O ₂ provided to the patient because of a significant dilution of oxygen with the NO-containing gas, while ensuring an effective treatment of vasoconstrictions related to hypoxemic respiratory distress PPHN type, ARDS or others.

The solution of the invention is then a gaseous drug comprising a mixture of nitrogen monoxide (NO) and nitrogen (N ₂ ) for use by inhalation to treat a hypoxemic respiratory distress related 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 distress being selected from acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension of the newborn (PPHN).

Depending on the case, the medicament of the invention may comprise one or more of the following technical characteristics:

the NO / N ₂ mixture is mixed, before its inhalation, 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 chosen from oxygen, air, air / oxygen mixtures, that is to say air supplemented with oxygen or an oxygen-containing gas, or mixtures nitrogen / oxygen.

the gaseous mixture NO / N ₂ contains at least 1300 ppmv of NO and nitrogen (N ₂ ) for the remainder, preferably at least 1400 ppmv of NO.

the gaseous mixture NO / N ₂ contains at least 1500 ppm of NO and nitrogen (N ₂ ) for the remainder.

the gaseous mixture NO / N ₂ contains less than 3500 ppmv of NO.

the gaseous mixture NO / N ₂ contains between 1500 and 4500 ppmv of NO.

the gaseous mixture NO / N ₂ contains from 1500 to 2500 ppmv of NO.

- The gas mixture NO / N ₂ is contained in a container of internal volume less than or equal to 12 liters (water equivalent).

the vessel containing the gaseous mixture NO / N ₂ is of cylindrical shape and comprises, at one end, a bottom and, at the other end, a neck with an outlet orifice at the level of which is fixed a device for controlling the passage gas and / or pressure reduction.

the gaseous mixture NO / N ₂ is contained in a gas cylinder.

the container containing the NO / N ₂ gas mixture comprises a neck with an outlet orifice at the level of which is fixed an integrated pressure reducing valve.

the gaseous mixture NO / N ₂ is stored in a vessel at a pressure of 100 to 500 bar absolute, preferably between 140 and 350 bar absolute.

the gaseous mixture NO / N ₂ is stored in a container equipped with a tap or an integrated pressure-reducing valve.

the gaseous mixture NO / N ₂ is stored in a cylindrical container having a diameter of between 5 and 40 cm and a height of between 10 and 80 cm.

- the treated human is an adult, a child or a newborn.

the gaseous mixture NO / N ₂ is diluted with an oxygen-containing gas in a ventilatory circuit of a respirator or a medical ventilator.

the gaseous mixture NO / N ₂ is delivered continuously in the ventilator circuit of the ventilator.

alternatively, the gaseous mixture NO / N ₂ is delivered in a pulsed manner into the ventilator circuit of the ventilator.

The present invention will now be better understood from the description given hereinafter with reference to the attached figure showing an embodiment of an NO distribution installation that can be used in the context of the present invention.

It shows a NO distribution facility that can be used to administer a high concentration NO and nitrogen gas mixture, ie 1200 ppm or more, of preferably between 1500 and 4500 ppm, to a patient P with hypoxemic respiratory distress with Fi0 ₂ around 100%, for example an adult suffering from ARDS or a newborn suffering from persistent pulmonary hypertension

This installation comprises a fan 1 comprising a breathing circuit or patient circuit 2 with two branches, that is to say with an inspiratory branch 3 and an expiratory branch 4. The inspiratory branch 3 is designed to convey breathing gas from the ventilator 1 to the patient P, while the exhalation branch 4 is designed to route the exhaled gas by the patient P to the ventilator 1.

At the level of the patient P, the administration of the gas is done by means of a patient interface 11, for example a respiratory mask, a cannula or a tracheal tube.

The fan 1 is supplied via a first connection line 10 with air (content 0 ₂ of 21% by volume) coming from an air source 7 and via a second connection line 10 'with air oxygen from an oxygen source 7 ', such as an oxygen cylinder or a pipe conveying oxygen from an oxygen production unit, such as a pressure-modulated unit (PSA), or an oxygen storage unit, such as a buffer or storage tank.

The oxygen-rich gas is delivered by the ventilator 1 into the inspiratory branch 3 of the patient circuit 2.

Furthermore, an NO delivery device 5 is fluidly connected to said inspiratory branch 3 of the patient circuit 2 to deliver, via a feed line 12, a NO / N ₂ mixture with a high NO concentration, that is, that is, at least 1200 ppm by volume, according to the present invention.

The NO delivery device 5 is itself supplied with a NO / N ₂ mixture, via a gas supply line 9, by a source of NO 6, such as a gas cylinder equipped with a tap or a built-in pressure reducer valve 8, preferably protected by a shock-proof cover.

The NO delivery device 5 makes it possible in particular to control the amount of NO / N ₂ released in the inspiratory branch 3, as well as the mode of release of this mixture, that is to say continuously or pulsed, by example only during the inspiratory phases of patient P.

It is therefore in the inspiratory branch 3, a dilution of the NO / N ₂ mixture with the 0 ₂ rich gas distributed by the fan 1.

The dilution is a function of the content of the initial NO / N ₂ mixture but also of the concentration of gas to be administered to the patient.

The gaseous mixture NO / N ₂ according to the invention is therefore an inhalable drug which can be used in combination with assisted ventilation 1 for treatment in particular of newborns of gestational age of at least 34 weeks, presenting a hypoxemic respiratory distress associated with clinical or echocardiographic signs of hypertension pulmonary artery, with the aim of improving oxygenation and avoiding the use of extracorporeal circulation oxygenation.

It can also be used to treat adults or children with ARDS.

The examples below give examples of mixtures that can be used in patients with ARDS or HPPN.

Example 1: Adult with ARDS

Tables 1 and 2 show the advantage of using high concentrations of NO in the initial mixture, all the more so since the NO target doses are high (eg non-responder patients requiring higher dosages than 20 ppmv) and that the F1O ₂ required are also high, that is to say of the order of 90 to 100%.

Indeed, such high F1O ₂ values can not be maintained for initial concentrations that are too low, ie less than about 1000 ppmv, and in this case, the positive effects of NO are counterbalanced by the effects. deleterious effects of dilution on F1O2. In general, the invention also relates to a therapeutic treatment method, in which a gaseous drug comprising a mixture of nitrogen monoxide (NO) and nitrogen (N ₂ ) is administered by inhalation to a patient suffering from hypoxemic respiratory distress related to pulmonary vasoconstriction, such as ARDS or HPPN, 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 new born.

Prior to its administration to the patient, the mixture of nitrogen monoxide (NO) and nitrogen (N ₂ ) is diluted with an oxygen-containing gas, preferably this dilution is performed in the ventilator circuit of a ventilator medical or similar.

In general, the following Table 1 shows the volumes (in ml) of NO / N ₂ administered in the inspiratory branch 3 of the patient circuit 2 of the ventilator 1 for a volume per minute of 10 1 / min of the ventilator (ie of air / 0 ₂ ), to obtain NO concentrations between 5 and 40 ppmv, as a function of the concentration of NO in the bottle containing the NO / N ₂ mixture, that is to say ranging from 100 to 3500 ppmv.

Table 1

As shown in Table 1, the administered volumes of NO for 5 ppmv dosages are 556 ml for a concentration of 100 ppmv NO and 14 ml for a concentration of 3500 ppmv, respectively. Similarly, for dosages of 40 ppmv, the volumes are 4444 ml for a concentration of 100 ppmv of NO and 114 ml for a NO concentration of 3500 ppmv.

This clearly demonstrates the value of using high concentrations of NO, that is at least 1200 ppmv, to reduce the impact of NO volume administered and associated dilution on ventilatory parameters (see Table 2) since the higher the concentration, the lower the volume of NO required.

Moreover, Table 2 illustrates the percentages (%) of dilution obtained for the NO concentrations of 100 to 3500 ppmv to obtain doses ranging from 5 to 40 ppmv, under the same conditions of administration as those of Table 1 (ie ventilation of 10 1 / min). Table 2

Table 2 (continued)

As can be seen, for the same treatment setpoint, the dilution becomes negligible for significant NO concentrations, that is to say at least 1200 ppmv, and therefore no longer influences the parameters and the ventilatory instructions. . In fact, the lower the volume of NO, the less it will modify the ventilation instructions and thwart the beneficial effects of the treatment, in particular the Fi0 ₂ .

According to the invention, it is therefore recommended the use of a gaseous mixture containing at least 1200 ppm by volume (ppmv) of nitrogen monoxide (NO), typically containing from 1200 to 4500 ppmv.

Finally, Tables 3 to 5 below show the impact of the dilutions on the desired FiO ₂ for initial NO concentrations in the 225, 450 and 2000 ppmv bottle.

The Fi0 ₂ is a very important parameter in the context of the pathologies treated with NO (refractory hypoxemia of the newborn, ARDS, etc.) since for these, FiO 2 of the order of 100% may be necessary.

This implies that the dilution should be as low as possible to keep Fi0 ₂ as high as possible and thus the beneficial effect of inhaled NO treatment. FiQ ₂ desired (%)

As can be seen in Tables 3 and 4 for initial low NO contents, ie 225 and 450 ppmv NO (nitrogen remainder), the losses of Fi0 ₂ generated by the dilution can represent approximately 20 to 30% of the Fi0 ₂ desired (ie the target Fi0 ₂ ), which becomes detrimental to NO treatment because a low Fi0 ₂ counteracts the positive effects of NO.

Conversely, as shown in Table 5, using a high concentration of NO (here 2000 ppm of NO in nitrogen) does not modify or negligibly (ie approximately <1%) the instructions of Fi0 _2. allowing to treat the patients with contents of 0 ₂ of almost 100% over short periods, to pass some extreme situations. While an increase in NO concentration in bottles may seem simple at first glance, it is not without problems related to the potential toxicity of high levels of NO (> 800 ppmv), since any overdose, due to for example, a bad dilution may lead to the administration of a toxic dose to the patient and, moreover, the higher the NO concentration, the greater the risk of formation of toxic compounds, such as the toxic NO ₂ that occurs form by oxidation of NO in the presence of oxygen.

In other words, the solution proposed by the invention goes against certain prejudices existing in the field concerned, which consider that the use of NO in high doses, that is to say more than 1200 ppmv , is dangerous and not recommended.

Claims

claims

A gaseous medicament comprising a mixture of nitrogen monoxide (NO) and nitrogen (N ₂ ) for use by inhalation to treat hypoxemic respiratory distress related to pulmonary vasoconstriction in humans, said gaseous mixture containing between 1200 and 4500 ppm by volume (ppmv) of nitric oxide (NO) and said hypoxemic respiratory distress being selected from acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension of the newborn (HPPN).

2. Medicament according to the preceding claim, characterized in that the gaseous mixture NO / N ₂ contains at least 1300 ppmv of NO and nitrogen (N ₂ ) for the rest.

3. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ contains less than 3500 ppmv of NO.

4. Medicament according to one of the preceding claims, characterized in that the mixture NO / N ₂ is mixed, before its inhalation, with an additional gas containing at least 21% by volume of oxygen.

5. Medicament according to claim 4, characterized in that the additional gas contains at least 50% by volume of oxygen.

6. Medicament according to claim 4, characterized in that the additional gas contains at least 80% by volume of oxygen, preferably 90 to 100% by volume of oxygen.

7. Medicament according to claim 4, characterized in that the additional gas is selected from oxygen, air, air / oxygen mixtures or nitrogen / oxygen mixtures.

8. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ contains at least 14300 ppmv of NO and nitrogen (N ₂ ) for the rest.

9. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ contains from 1500 to 2500 ppmv of NO.

10. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ is contained in a container of internal volume less than or equal to 12 liters (water equivalent), preferably the container is a bottle of gas.

11. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ is stored in a container at a pressure of 100 to 500 bar, preferably between 140 and 350 bar.

12. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ is stored in a container equipped with a tap or an integrated pressure reducer valve.

13. Medicament according to one of the preceding claims, characterized in that the gaseous mixture NO / N ₂ is stored in a cylindrical container having a diameter of between 5 and 40 cm, and a height of between 10 and 80 cm.

14. Medicament according to one of the preceding claims, characterized in that the treated human is an adult, a child or a newborn.