CH683485A5 - infusion solutions, preservation and organ perfusion. - Google Patents

Description

5

10

15

20

25

30

35

40

45

50

55

CH 683 485 A5

Description

The present invention relates to solutions for perfusion, preservation (or storage), and / or reperfusion of organs, including for heart transplants.

One of the main causes of failure of heart transplants comes from the risks of degradation, or even necrosis, of the graft which appear during the reoxygenation of the transplanted organ, and which are linked to ischemia generally prolonged between the beginning of implantation in the donor and the end of implantation in the recipient.

A four to five hour ischemia constitutes, for example in the case of the heart, the tolerable upper limit and does not exclude many accidents.

To limit this risk, many authors have proposed and used protective solutions both for the perfusion of the organ to be explanted and for its conservation at low temperature and its reperfusion during transplantation.

Examples of these solutions are the solutions

. Bretschneider HTK

. COLLINS

. ST THOMAS

. UW

. Stanford.

However, these solutions have only limited advantages and offer only partial protection against the risks which appear during reperfusion and which are partly attributed to the metabolic production of oxygen free radicals produced in abundant quantities, especially during reoxygenation of the ischemic organ.

The risk of oxidative cellular and membrane degradations resulting from the production of these radicals has been the subject of several studies in the field of myocardial protection by cardioplegia. These various studies have suggested the introduction, into the protective solutions used, of substances liable to oppose the production or effect of free radicals, and in particular antioxidant substances. Different compounds have been proposed, some, such as deferoxamine, allopurinol, catalase, Peroxidase, as being capable of opposing the production of free radicals, others, such as superoxide dismutase, which can destroy these radicals, d still others, such as vitamin E or equivalents (Trolox) being capable of "neutralizing" free radicals.

Among these latter compounds are also molecules carrying thiol groups such as N-acetylcysteine or reduced glutathione (GSH), which has been considered as a "scavenger" of free radicals. However, the literature is divided on the interest of glutathione.

Thus G.W. Standeven et al., In J. Thorac. Cardiovasc. Surg. 1979, 78, 893-907 Cold-Blood potassium cardioplegia, found little difference in the level of protection offered by the addition of glutathione.

On the other hand, M. Bernier et al, in Reperfusion-induced Arrhythmias and Oxygen-derived Free Radicate, Circulation Research, Vol. 58, n ° 3, March 1986, 331-340, note that the addition, in the isolated perfused heart of rats, of L-methionine, of superoxide dismutase, of catalase, of mannitol, of glutathione, or of deferoxamine, the risk of fibrillation or ventricular tachycardia during reperfusion.

JC Chatham et al., In Depletion of Myocardial Glutathione: Its effects on heart function and meta-bolism during ischaemia and reperfusion, Cardiovascular Research, 1988, 22, 833-839, conclude that a depletion of glutathione during ischemia of rat hearts, does not seem to result in an aggravation of the metabolic attack.

A. Blaustein et al., In Myocardial Glutathione Depletion Impairs Recovery After Short Periods of Ischaemia, Circulation, Vol. 80, n ° 5, November 1989, conclude that a depletion in the heart of a rat isolated in glutathione, obtained by injection of diethyl maleate, results in a less recovery of systolic function and that an improvement can be obtained in the event of reperfusion by a solution supplemented with glutathione.

A. Singh et ai., In Relation Between Myocardial Glutathione Content and Extent of Ischaemia -Reperfusion Injury, Circulation, Vol. 80, no. 6, December 1989, 1795-1803, show an increase in the GSH content in pigs infused intravenously with glutathione five minutes before and during cardiac reperfusion, and note an improvement in local recovery.

W. N. Wicomb et al., In Rôle of Glutathione in 24hour Heart Storage by Microperfusion Using a New Polyethylene Glycol Solution, J. Mol. Cell Cardiol. 22 (supplement V) 1990, p. 82, report an improvement in the recovery of the isolated rabbit heart preserved in a protective solution comprising glutathione GSH, the simple addition of glutathione during reperfusion not being effective.

V. Kantamneni et al., In Extended Preservation of Canine Myocardium Using UW Solution, J. Mol. Cell Cardiol. 1990 (Suppl. V); 22:22 (Abstr) conclude that solutions (UW solutions and modified UW solutions), containing glutathione, which show some effectiveness in the preservation of isolated organs such as the liver, kidney and pancreas, do not provide significant improvements over the modified Collins solution not containing this compound and that these solutions could not significantly increase the duration of heart preservation in dogs.

2

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 683 485 A5

The addition of N-acetylcysteine is studied by M. B. Forman, Glutathione Redox Pathway and Reperfusion Injury, Circulation, Vol. 78, no.1, July 1988, 202-213. He suggests that treatment with N-acetycysteine (NAC) before reperfusion may improve postischemic recovery.

If it may therefore appear interesting to use substances acting against the production or the effect of free radicals in the myocardium in the context of cardioplegic protection, the choice of the compound and the methods of implementation do not seem obvious and the addition of these compounds, including glutathione, in myocardial infusion and reperfusion solutions in daily hospital practice did not lead to decisive results.

Ph. Menasché et al., In Free Radical Trappers in Myocardial Protection in Cardiac Surgery, Ann. Cardiol. Angéiol; 1986, 35 (no. 7bis), 747-452, however conclude that the preservation of the post-ischemic left ventricular function, due to a given cardioplegic solution, could be significantly improved by the addition of antioxidants capable of preventing formation free radicals or destroy or neutralize them. On the other hand, the choice of the most effective antioxidant among the many candidates including superoxide dismutase SOD, Peroxidase and glutathione is not obvious, not to mention possible side or toxic effects. A fortiori when one passes from the field of cardioplegia, in which the durations of ischemia are relatively short, to the field of transplantation, the literature does not provide any really usable indication on the choice and the methods of implementation of solutions. protective genuinely effective.

The present invention proposes to solve these problems and to provide remarkably effective protective solutions for the preservation of organs, with a view to surgical operations and in particular transplantation. Target organs include the heart, as well as other organs, including the liver, lung, and kidney.

The present invention provides, for this purpose, a perfusion and storage solution for the ex-planted organ and a reperfusion solution for the organ being implanted, both characterized by the inclusion of at least an antioxidant compound, which can be a scavenger of free oxygen radicals, said solutions having a partial pressure of oxygen which is zero or very low and is maintained substantially at this value until use.

In a particularly preferred manner, the free radical scavenger compound is a compound comprising thiol functions. Among the preferred thiols, there is reduced glutathione (GSH) or its precursors or related substances and in particular N-acetylcysteine (NAC), glutathione analogs and in particular gluthation monoester.

Other compounds with a thiol function can be used, in particular diethyldithiocarbamate, its analogs and derivatives, as well as inhibitors of the converting enzyme.

Another compound useful in the invention is vitamin E or its analogs or derivatives.

According to the invention, the solutions are prepared and stored away from oxygen in the air, for example being prepared in degassed solutions, preferably under a nitrogen atmosphere. The solutions according to the invention are stored and preserved in airtight containers such as bottles or, preferably, airtight plastic bags, for example in laminated composites of a type known per se.

Advantageously, the solutions according to the invention may also comprise, in addition to the anti-radical thiols, a compound opposing the formation of radicals such as metal chelators and in particular deferoxamine (INN).

By reduced value of the oxygen concentration in accordance with the invention is preferably meant a maximum dissolved oxygen concentration of less than 0.1 ppm.

In the case where glutathione is used, the reduced glutathione content of the solution is preferably of the order of 0.5 to 10, and advantageously of 3 mmol / l. In the case where the thiol is NAC, the content is preferably of the order of 10 to 80, and advantageously of 40 mmol / l.

The invention is preferably implemented in different forms depending on whether it is applied either to the perfusion and to the preservation of the explanted organ, or to the reperfusion of the implanted organ.

In the case of an infusion and preservation preparation according to the invention, the solution is constituted so as to prevent the formation of cellular edema and the appearance of oxidative lesions, while limiting calcium overload. In addition, for certain organs and in particular the heart, the solution is capable of playing the role of metabolic inhibitor.

Advantageously, the calcium content is low, preferably less than 0.5 mM, and it is preferred that the solution contains magnesium, at a content, preferably, greater than 10 mM. In addition, a lower pH is preferred, in particular 7.40 ± 0.40. In the case where the perfusion and preservation solution is intended for the cardiac organ, a potassium concentration is provided, preferably at least equal to 10 mM, the potassium possibly being absent for the other organs.

In one of the particularly effective and advantageous embodiments of the invention, an infusion and preservation (storage) solution of the cardiac organ according to the invention comprises the following compounds:

3

5

10

15

20

25

30

35

40

45

50

55

CH 683 485 A5

A Infusion and storage solution (1)

Component

Concentration (mmol / liter)

K +

10-30

Na +

90-120

Mg ++

10-20

Ca ++

0.005-1.2

this-

100-160

Mannitol

50-200

Glutamate

4-26

NAC

10-80

or GSH

0.2 to 0.5-10

osmolarity

270-450 (e.g. 370) mOsm / l pH

7.40 ± 0.40 (at 20 ° C)

In the case of a reperfusion preparation according to the invention, the solution is constituted so as to continue to limit cellular edema and oxidative damage. It is also planned to restore calcium homeostasis. The preferred pH is 7.70 ± 0.30. In the case of the heart, it is formed so as to prolong metabolic inhibition and will retain potassium at a concentration, preferably, greater than 10 mM.

Thus, in an advantageous embodiment, the reperfusion solution comprises the following compounds:

B Reperfusion solution (2)

Component

Concentration (mmol / liter)

K +

10-30

Na +

90-120

Mg ++

0-20

Ca ++

0.005-1.2

this-

100-160

Mannitol

50-200

Glutamate

4-26

NAC

10-80

or GSH

0.2 to 0.5-10

Osmolarity

270 to 450 (e.g. 370) mOsm / l pH

7.70 ± 0.30 at 28 ° C

4

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 683 485 A5

The preferred embodiment of the infusion and preservation solution is:

C Infusion and storage solution (1)

Component

Concentration (mmol / liter)

K +

12

Na +

100

Mg ++

13

Ca ++

0.25

this-

110.4

Mannitol

109.8

Glutamate

20

GSH

0.5 to 3

Osmolarity

370 mOsm / l pH

7.40 (at 20 ° C)

and the preferred embodiment of the reperfusion solution is D Reperfusion solution (2)

Constituent Concentration (mmoie / liter)

K +

14.9

Na +

100

Mg ++

-

Ca ++

1.2

Cl-

97.5

Mannitol

136

Glutamate

20

GSH

0.5 to 3

Osmolarity

370 mOsm / l pH

7.70-28 ° C

Of course, the compounds thus defined can be replaced by compounds having equivalent functions, the molar contents preferably remaining substantially unchanged.

Glutamate, whose function is to stimulate anaerobic energy production by myocardial cells, can be replaced in particular by aspartates, succinates, fumarates and malates.

Mannitol, an impermeable agent whose function is to limit edema, can be replaced by other substances playing an impermeable role in the interstitial medium, increasing osmotic pressure such as lactobionate (by reducing the chloride concentration in proportion), raffinose, sucrose. Since the selected waterproofing substance must not be metabolized or picked up by the organ, mannitol is suitable for the heart while it will be excluded for the liver.

The relatively acidic pH of the infusion and storage solution, preferably of the order of 7.40 at 28 ° C, is preferably carried out without buffer.

The pH of the reperfusion solution, preferably adjusted to 7.70 at 28 ° C., can optionally be achieved using a buffer (in particular bicarbonate, histidine).

Preferably, the two solutions according to the invention are presented, in a single packaging, in the form of one or more containers per solution, preferably deformable bags with air-impermeable walls with a total volume of 1500 to 2000 ml.

Other advantages and characteristics of the invention will appear on reading the following description, given by way of nonlimiting example.

5

5

10

15

20

25

30

35

40

45

50

55

CH 683 485 A5

1. Preparation of the infusion and storage solution

A degassed sterile pyrogen-free aqueous medium is prepared, under conditions protected from atmospheric oxygen, and having composition C.

This composition has on average a maximum concentration of dissolved oxygen <0.1 ppm and a pH of 7.40 at 20 ° C. This solution is packaged in plastic bags impermeable to atmospheric oxygen or in plastic bags permeable to oxygen, but themselves contained in a bag of a plastic-aluminum complex which is impermeable to atmospheric oxygen.

2. Preparation of the reperfusion solution

By taking the same precautions as in Example 1, a reperfusion solution having composition D is prepared.

This composition can contain a bicarbonate buffer, or histidine maintaining the pH at 7.70 at 28 ° C.

This solution is put into similar bags with a volume of 100 ml.

3. Test of solutions containing NAC on preparations of isolated rat hearts

Fifty isolated isovolumic heart preparations of 300 gram Sprague-Dawley rats were used, which were quickly connected to a non-recirculating Langendorff infusion column to establish a retrograde infusion using an oxygenated Krebs-Henseleit buffer. (95% O2, 5% CO2) to establish a retrograde perfusion at a pressure of 100 cm of water. The left ventricular pressure, its derivative and the end of diastole pressure were recorded continuously. Coronary flow was measured by collection of venous coronary flow. Left ventricular pacing was maintained at the frequency of 320 / min.

After a twenty-minute control period, thirty hearts were stopped by infusion using the 4 ° C infusion preservation solution, then quickly placed in glass containers filled with the same solution and surrounded by ice. . The hearts were kept there for five hours with an average myocardial temperature of 2 ° C at the end of storage. The hearts were then reconnected to the perfusion circuit and subjected to an additional one hour ischemia between 15 and 18 ° C. The hearts were divided into three groups, including a control group which received a first infusion of an identical solution but devoid of NAC at the establishment of post-storage ischemia and an additional infusion of 25 ml of this solution immediately before aortic de-clamping, the infusions being performed at 4 ° C and 8 ° C respectively. The same protocol was followed for the second group of hearts except for the fact that the solution contained 0.4 M NAC. In the third group, a solution containing NAC at 28 ° C. was distributed in a single dose to the end of ischemia. In this latter group, the concentration of NAC was adjusted to 0.072 M so that all the treated hearts received the same amount of this substance, that is to say approximately 1.80 millimole. The vials containing the solutions as well as the tubes were protected from light to prevent oxidation. In the three groups, the infusions after storage were delivered at a pressure of 30 cm of water. After a duration of ischemia of six hours, the hearts were re-perfused for one hour at 37 ° C.

For all three groups, stimulation was stopped and the left intraventricular balloon deflated during the ischemia period to simulate clinical conditions. After reperfusion, the stimulation was restored. Isovolumetric measurements of coronary flow, left ventricular pressure, its first derivative and telediastolic pressure were taken three times during the control period and then during minutes 5, 30, 45 and 60 of the reperfusion.

The results were as follows:

- Coronary flow: after sixty minutes of reperfusion, the flow of all hearts was significantly reduced (p <0.001) compared to the pre-ischemic control values. However, the best recovery of coronary flow was found in the groups treated with NAC (table

I).

- Left ventricular function: the left ventricular pressure decreased significantly after ischemia and reperfusion in the hearts of the three groups (Table I). However, the hearts of the control group (group I) and those having received only the NAC-supplemented reperfusion at the end of the ischemic episode after storage (group III) reflected significantly greater losses of pressure (p <0.001) than those protected by the multidose solution enriched with NAC (group

II) during the last hour of global ischemia (p <0.01). Also during the whole reperfusion period, significantly greater pressure was developed in group II. The effects of the treatment on the post-ischemic dP / dt derivative were similar to those of the developed pressure and the most important values were obtained for group 11.

- Left ventricular diastolic pressure: at the end of the stop-storage-ischemia protocol, the hearts of control group I as well as those of group III suffered a significant loss of compliance. On the contrary, post-ischemic contracture was notably reduced in group II.

The results of this experiment demonstrate the important advantage of implementing the so6

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 683 485 A5

protective lutions according to the invention in a realistic model extrapolable to the field of human transplants.

4. Testing of solutions containing GSH on preparations of isolated rat hearts

The tests are carried out on preparations of rat hearts, with isovolumetric contraction, divided into three groups 1, 2, 3. Cardiac arrest is obtained by infusion of the infusion solution and storage at + 4 ° C. The hearts are then stored by immersion for 5 h in the solution at + 2 ° C. An ischemia period of one hour at 15-18 ° C is then established, with initial infusion with administration of the infusion solution and storage at the start of this ischemia period and administration of the reperfusion solution at the end of the hour of ischemia, that is to say immediately before the aortic declamation page. The temperatures of the solutions are 4 and 28 ° C, respectively. They are administered under a pressure of 30 cm H2O. After the ischemia period, the hearts are reperfused for one hour at 37 ° C.

The solutions used are as follows:

Group 1 (control): solution identical to solution C, but devoid of GSH, then solution D, devoid of GSH,

Group 2: solution C, then solution D,

Group 3: solution D, supplemented with deferoxamine, then solution D supplemented with deferoxamine.

The results appear in Table II. They show the spectacular improvement produced by solutions C, characterized by the presence of GSH and the low oxygen concentration.

In the picture:

CF

= coronary flow (ml / min),

Pdiast =

= diastolic pressure (mm Hg),

Pdev

= developed pressure (mm Hg),

dP / dt =

= first pressure derivative (mm Hg.sec_1)

5. Implementation of solutions in human heart transplantation

The solutions are prepared according to Examples 1 and 2. After establishing transthoracic access to the explanted heart, 1000 to 2000 ml of solution C at 4 ° C are perfused into the cardiac organ by the aortic route for three to four minutes. The heart is removed, then placed in a jar provided for this purpose so as to be immersed in solution C and the jar is cooled to the usual storage temperature of + 4 ° C.

The graft being transported to the prepared recipient and under extracorporeal circulation, a heart transplant is carried out and, during this operation, an antero or retrograde infusion of solution C at + 4 ° C is repeated to support cardiac arrest. The volume of infusion is generally of the order of 1000 to 2000 ml.

At the end of the placement of the graft, the heart is reperfused by the aortic route using solution D at 28-27 ° C for a period of 5 minutes on average, the volume used being of the order of 1000 ml. At the end of this infusion, the aorta is unclamped, the circulation is restored and the extracorporeal circulation is weaned in the usual way.

Table I

Effect of NAC on coronary flow and developed left ventricular pressure

Coronary flow group (ml / min) Left ventricular developed pressure (mm Hg)

N = 10 Normal Reperfusion Normal Reperfusion

Control, NAC-free solution

14.6 +

0.8

10.5 ± 0.4

130.7 ± 2.1

63.6 ± 3.3

Second group (0.04 M) NAC

14.8 +

0.6

12.1 ± 0.5 *

126.4 ± 2.8

101.5 ± 3.4 ***

Third group (0.07 M) NAC

16.0 +

0.5

13.4 ± 0.4 "

129.7 + 2.0

69.8 + 3.6

* p <0.05 compared to the control cardioplegia.

** p <0.01 compared to control cardioplegia.

*** p <0.001 compared to control cardioplegia and NAC-enriched reperfusion.

7

5

10

15

20

25

30

35

40

45

50

55

CH 683 485 A5

Table II

A. Analysis of variance (I) CF (ml / min) (n = 7)

1) Group 1 = 12.6 ml / min ± 0.5 ml / min

2) Group 2 = 14.2 + 0.4 ml / min

3) Group 3 = 10.6 ± 0.4 ml / min Line effect (lines) F> 19.1173 => p <0.001 Column effect (time) F> 6.3592 => p <0.001

(1) versus (3) p <0.01

(2) versus (3) p <0.001

(II) Pdiast (mmHg) (n = 7)

Group 1 = 33.1 ± 2.9 mmHg Group 2 = 16.9 ± 1.4 mmHg Group 3 = 21.7 ± 2.2 mmHg Line effect = F> 13.1426 p <0.001 Time effect = N.S.

(1) versus (2) p <0.001

(1) versus (3) p <0.01

(2) versus (3) N.S.

(III) Pdev (mmHg) (n = 7)

Group 1 = 84.0 ± 3.0 mmHg

Group 2 = 104.5 ± 4.1 mmHg

Group 3 = 116.8 ± 3.6 mmHg

Line effect F> 20.6411 p> 0.001

N.S. column effect

(1) versus (2) p <0.001

(1) versus (3) p <0.001

(2) versus (3) N.S.

(IV) dP / dtmax (+) (n = 7)

Group 1 = 2932 ± 96 mmHg sec-1

Group 2 = 3418 ± 122 mmHg sec-1

Group 3 = 3479 ± 173 mmHg sec-1

Line effect F> 4.7966 p <0.01

N.S. column effect

(1) versus (2) p <0.05

(1) versus (3) p <0.05

(2) versus (3) N.S.

8

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 683 485 A5

B. Scheffé test at 60 minutes of reperfusion

(I) CF (ml / min) (n = 7)

Group 1 = 11.3 ± 0.8 ml / min Group 2 = 12.6 ± 0.8 ml / min Group 3 = 8.9 ± 0.7 ml / min

(1) versus (3) N.S.

(2) versus (3) p <0.02

(II) Pdiast (mmHg) (n = 7)

Group 1 = 30.4 ± 5.0 mmHg Group 2 = 14.9 + 1.9 mmHg Group 3 = 19.6 ± 4.0 mmHg (1) versus (2) p <0.05

(1) versus (3) N.S.

(2) versus (3) N.S.

(III) Pdev (1) mmHg (n = 7)

Group 1 = 80.1 ± 5.3 mmHg Group 2 = 107.6 ± 8.5 mmHg Group 3 = 120.7 ± 8.9 mmHg (1) versus (2) p <0.05

(1) versus (3) p <0.01

(2) versus (3) N.S.

(IV) dP / dt max (mmHg sec-1) (n = 7)

Group 1 = 2714 ± 110 mmHg sec-1 Group 2 = 3429 ± 260 mmHg sec-1 Group 1 = 3500 ± 300 mmHg sec-1

(1) versus (2) p <0.05 (1) versus (3) p <0.05

(2) versus (3) N.S.

C. Comparison of the control values with the values measured after 60 min of reperfusion (Student test)

(I) CF (ml / min)

Group 1 = 14.4 ± 0.7 versus 11.3 + 0.8ml / min p 0.05 Group 2 = 15.0 + 0.4 versus 12.6 ± 0.8ml / min p 0.05 Group 3 = 15.1 ± 0.3 versus 8.9 ± 0.7 ml / min p 0.001

9

5

10

15

20

25

30

35

40

45

50

55

60

CH 683 485 A5

(II) Pdiast (mmHg)

(1) 11.3 ± 0.7 versus 30.4 ± 5.0 mmHg p <0.01

(2) 10.6 ± 0.7 versus 14.9 mmHg ± 1.9 N.S.

(3) 9.6 ± 0.5 versus 19.6 ± 4.0 mmHg p <0.05

(III) Pdev (mmHg)

Group 1 = 132.1 ± 3.1 versus 80.1 ± 5.3 mmHg p <0.001

Group 2 = 134.4 ± 2.7 versus 107.6 ± 8.5 mmHg p <0.05

Group 3 = 149.3 ± 2.9 versus 120.7 ± 8.9 mmHg p <0.05

(IV) dP / dt max (mmHg sec-1)

(1) 4281 ± 147 versus 2714 ± 110 mmHg sec-1 p <0.001

(2) 4714 ± 200 versus 3429 ± 260 mmHg sec-1 p <0.01

(3) 4191 ± 289 versus 3500 ± 300 mmHg sec-1 N.S.

Claims (19)

Claims 1. Organ perfusion and preservation and / or reperfusion solutions, including the cardiac organ, characterized by the inclusion of at least one antioxidant compound and by zero or very low partial pressure of oxygen and now substantially at this value lowered until use. 2. Solutions according to claim 1, characterized in that the antioxidant compound is a free radical scavenger such as a compound comprising thiol functions. 3. Solutions according to claim 2, characterized in that the thiol is glutathione in the reduced state (GSH) or its precursors or glutathione monoester. 4. Solutions according to claim 2, characterized in that said free radical scavenger compound is N-acetylcysteine (NAC) or diethyldithiocarbamate. 5. Solutions according to any one of claims 1 to 4, characterized in that they are packaged in flasks or flexible bags impermeable to air. 6. Solutions according to any one of claims 2 to 5, characterized in that they comprise, in addition to an anti-free radical thiol, a compound opposing the formation of radicals, in particular deferoxamine (INN) or other metal chelator. 7. Solutions according to any one of claims 1 to 6, characterized in that the maximum concentration of dissolved oxygen is 0.1 ppm or less. 8. Solutions according to claim 3, characterized in that the reduced glutathione concentration is between 0.5 and 10 mmol / l and in particular of the order of 3 mmol / l. 9. Solutions according to claim 4, characterized in that the NAC content is between 0.01 mol / l and 0.08 mmol / l, and in particular of the order of 0.04 mol / l. 10. Infusion and preservation solution according to any one of claims 1 to 8, characterized in that it comprises at least one component such as an impermeable agent preventing the formation of cellular edema, and means limiting the overload. calcium, said solution having a pH of the order of 7.40 ± 0.40. 11. perfusion and preservation solution according to claim 10, for the heart, characterized in that it contains at least one metabolic inhibitor component, in particular potassium. 12. Infusion and preservation solution according to one of claims 10 and 11, characterized in that it contains the following components: 10 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 683 485 A5 10 at 30 mmol / liter K + 90 at 120 mmol / liter Na + 10 at 20 mmol / liter Mg2 + 0.005 at 1.2 mmol / liter Ca2 + 100 at 160 mmol / liter above 50 at 200 mmol / liter mannitol 4 at 26 mmol / liter glutamate and 10 at 80 mmol / liter N-acetylcysteine or 0.2 at 10 mmol / liter glutathione in the reduced state. 13. Infusion and preservation solution according to claim 12, characterized in that, for the liver, it does not contain mannitol, but another waterproofing agent. 14. reperfusion solution according to any one of claims 1 to 8, characterized in that it comprises a constituent such as an impermeable agent capable of preventing the formation of cellular edema, and means restoring calcium homeostasis, the solution having a pH of the order of 7.70 ± 0.30. 15. A reperfusion solution for the heart, according to any one of claims 1 to 8, characterized in that it comprises a constituent such as an impermeable agent capable of preventing the formation of cellular edema as well as an inhibiting constituent metabolic, especially potassium. 16. A reperfusion solution according to any one of claims 14 and 15, characterized in that it contains the following components: 10 at 30 mmol / liter K + 90 at 120 mmol / liter Na + 0 at 20 mmol / liter Mg2 + 0.005 at 1.2 mmol / liter Ca2 + 100 at 160 mmol / liter above 50 at 200 mmol / liter mannitol 4 at 26 mmol / liter glutamate and 10 at 80 mmol / liter N-acetylcysteine or 0.2 at 10 mmol / liter glutathione in the reduced state. 17. reperfusion solution according to claim 16, characterized in that the mannitol is replaced by lactobionate or sucrose, and / or glutamate is replaced by aspartate or succinate or fumarate or ie malate. 18. A reperfusion solution according to claim 16, characterized in that, for the liver, it does not contain mannitol, but another waterproofing agent. 19. Solutions according to any one of claims 1 to 18, characterized in that they are in the form of bottles or separate bags, in a single packaging, namely respectively the infusion and preservation solution and the reperfusion solution . 11