AU2015202494B2 - A composition comprising nor-adrenaline and a NET inhibitor for administering to a brain-dead, heart-beating potential organ donor - Google Patents

Abstract

A composition for intravascular administration for treatment of a brain-dead, heart-beating, respirated potential organ donor for maintaining hemodynamic stability, comprising: adrenaline, nor-adrenaline and a NET inhibitor.

Description

- 1 A composition comprising nor-adrenaline and a NET inhibitor for administering to a brain-dead, heart-beating potential organ donor TITLE A composition, an infusion solution, a method and a kit for administration of the 5 solution FIELD OF INVENTION The present invention relates to a method of handling a potential organ donor immediately after brain death and until organs are harvested, and a composition and an infusion solution. 10 BACKGROUND OF THE INVENTION It is well known that there is a great shortage of donor organs, which are suitable for transplantation. Hemodynamic instability during and after brain death of a heart-beating donor is often associated with the deterioration of graft viability, leading to organ exclusion. 15 There is a need for a method of treating the potential organ donor after brain death and before harvesting of organs, which decreases the rejection rate of organs that are harvested from such donor. Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common 20 general knowledge in the field. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to mitigate, alleviate or eliminate one or more of the above-identified deficiencies and disadvantages singly or in any combination. 25 It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

-2 According to a first aspect the invention provides a composition for intravascular administration for treatment of a brain-dead, heart-beating, respirated potential organ donor for maintaining hemodynamic stability, comprising: adrenaline, nor-adrenaline and a NET inhibitor. Unless the context clearly requires otherwise, throughout the description and the 5 claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". In certain preferred embodiments of the present invention, the NET inhibitor is desipramine or imipramine. 10 According to an aspect of the invention, there is provided a composition for intravascular administration for treatment of a brain-dead, heart-beating, respirated potential organ donor, comprising: nor-adrenaline and a NET inhibitor. In an embodiment, the NET inhibitor may be cocaine or a stimulating analogue thereof. In another embodiment, the NET inhibitor may be at least one tricyclic 15 antidpressant included in the group comprising: Amitriptyline (ELAVIL); Clomipramine (ANAFRANIL); Doxepin (ADAPIN, SINEQUAN); Imipramine (TROFANIL); Trimipramine (SURMONTIL); Amoxapine (ASENDIN); Desipramine (NORPRAMIN); Maprotinile (LUDIOMIL); Nortriptyline (PAMELOR); and Protriptyline (VIVACTIL). In a further embodiment, the NET inhibitor may be at least one agent included in the 20 group comprising: Venlafaxin (EFFEXOR); Atomexetine (WELLBUTRIN); Duloxetine (CYMBALTA); Mirtacapine (REMERON); Norclomipramine; Oxaprotiline; Lofepramine; Reboxetine; Maprotiline; Nomifensine; Doxepin; Mianserin; Viloxazine; Mirtazapine; and Nisoxetine. According to a still further embodiment, the composition may further comprise at 25 least one of: adrenaline, hydrocortisone, thyroxin, insulin, triiodotyronine, a vasopressor agent, such as desmopressin, and methylprednisolone. The NET inhibitor may be present in an amount of 0.2 to 5 times of the amount of nor adrenaline. In the case of cocaine, the ratio between cocaine and nor-adrenaline may be about 1:1.

-3 In another aspect, there is provided an infusion solution comprising the composition mentioned above and a pharmaceutically acceptable medium, such as pure water, Ringer's acetate solution or physiological sodium chloride solution. The composition may be dissolved in the pharmaceutically acceptable medium in an amount of about 1 mg of nor-adrenaline, and 5 about 1 mg of cocaine in about 50 ml of fluid. In a further aspect, there is provided a method for treatment of a brain dead, heartbeating, respirated potential organ donor, comprising: infusion of the infusion solution mentioned above, in an amount sufficient for maintaining a mean arterial pressure of about 60 mmHg. 10 In a still further aspect, there is provided a kit for intravenous administration for treatment of a brain dead, heart-beating, respirated potential organ donor, comprising: an infusion bag comprising an infusion solution as mentioned above; an infusion pump for pumping the infusion solution to a needle inserted into the vascular system of the donor for 20 controlling the amount of infusion solution entered into the donor and tubings for 15 interconnecting the bag, pump and needle. The kit may comprise several sets of infusion bags, infusion pumps and tubings. The kit may further comprise a computer for controlling the pump or pumps, whereby the computer is operated according to a predetermined control strategy. In a yet further aspect, there is provided a method of infusing a solution into the circulation system of a brain dead, heart-beating, respirated potential organ donor, comprising: 20 determining that the donor is brain dead; continuing or initating respiration for oxygenation of the blood; infusion of an infusion solution as mentioned above; and controlling the infusion by means of a computer. BRIEF DESCRIPTION OF THE DRAWINGS 25 Further objects, features and advantages of the invention will become apparent from the following detailed description of embodiments of the invention with reference to the drawings, in which: Fig. I is a schematic view of a nerve terminal; Figs. 2, 3 and 4 are diagrams showing blood pressures during treatment with the 30 compositions according to embodiments; 4 Fig 5 is a schematic diagram of a kit for administration of an infusion solution according to etmbodiments; Fig, 6 is a schematic diagram of another kit for administration of infusion solutions according to embodiments, DETAILED DESCRIPTION OF EMB3ODIMENTS Below, several embodiments of the invention will be described, These embodiments are described in illustrating purpose in order to enable a skilled person to carry out the invention and to disclose the best mode. However, such enbodiments do not limit the scope of 10 the invention, Moreover, certain combinations of features are shown and discussed. However, other combinations of the different features are possible within the scope of the invention. Definitions: In the context of the present description and embodiments the following definitions apply: The tern "cocaine analogue" is intended to mean an analogue, which acts in the same or a similar way as cocae in preserving the organs in a brain-dead, heart-beating, 15 respirated donor before harvesting of the organs, The term "Pharmaceutically acceptable" means a non-toxic material that does not decrease the effectiveness of the biological activity of the active ingredients, Such pharmaceutically acceptable buffers, carriers or recipients are well-known in the art, see for example Reningtods Pharmaceutial Sciences, 18th edition, A,R Gennaro, Ed., Mack Publishing Company (1990) and handbook of Pharmaceutical 20 Excipiens, 3rd edition, A. Kibbe, Ed, Pharmaceutical Press (2000), The term "physiologically acceptable solution" means a solution that does not interfere substantially with the fluids in the body, An object of the below described embodiments is to improve the outcome of organ harvesting and transplantation from a donor, which has been declared brain-dead but still has a 25 beating heart and which s ventillated., The process of becoming brain dead is a traumatic experience for the body and its organs, Thus, a thorough understanding of the endocrinal, hormonal and metabolic events before, during aid after declaration of brain death would, be of interest for determining intervention, 30 Brain death may be initiated by a nassive necrosis of brain cells, which may be due to different causes, Such necrosis may result in increased osmotic pressure in the brain, resulting in water absorptin via the blood-brain barrier, Since the scull cannot expand, the intracranial pressure rises considerably, When the intracranial pressure exceeds the systolic blood pressure, the brain is 35 exposed to an ischenic condition, because blood cannot enter the brain. The brain may react by increasing the heart rate and blood flow and by increasing the systemic vascular resistance.

5 In addition, the adrenal gland increases the level of circulating adrenalin (epinephrine) and nor-adrenaline (nor-epinephrne). This is called the Cushing reflex, 'The heart rate may increase by several hundred percent, to a maximum heart rate. The blood pressure may increase to above 200 nng, This massive reaction is also called the 5 catecholaminee storm" or "sympathetic autonomous stormC The adrenaline and/or nor adrenaline levels may increase by 70 times, as described in more detail below. if this increase of systolic blood pressure is insufficient for delivering blood to the brain, the brain will maintain its ischemic state, However, the brain cannot sustain more than about 10 minutes without flood supply, 10 If the intracranial pressure, for example due to the increased osmotic pressure, rises to more than about 300 mmi-ig, the brain cannot withstand such high pressures but disintegrates. The end result will be a progressive brain swelling, and herniation of the hipocampal gyri with lateral pressure of the brainstem, with eventual loss of brainstem fun action and loss of spontaneous respiration. This may results in hemiation of he brain stem 15 through the firanen magnun. Other causes of (brain) death. may result in somnewhat different processes. In Sweden, brain death is defined as irreversible loss of function of the entire brain including the brinstern, There are several indicia of brain death, which are of less interest for the present embodiments, However, after brain death, there is no cerebral blood circulation 20 and no spontaneous respiration. The body temperature should be above 33"C and there s ould be no drug intoxication After brain death, the brain, including the brain stem, cannot retain its function, because it is permanently damaged. During the "catecholaine storm", the levels of adrenaline and nor-adrenaline may 25 rise considerably, During experiments on dogs, an increase in blood concentration of adrenaline from about 0,40 to 5 nnol/l and an increase of nor-adrenaline from about 0.40 to 12 nmol/1 were obtained within one to three minutes. After occurrence of brain death, the hypothalamic-pituitayadrenal axis is disrupted. However, necrosis is followed by a release of cy okinec, especially L-6, which stimulates the 3O adrenal gland to produce adrenaline and nor-adrenaline, Eventually, the production of these inotropics will be reduced and after some 60 minutes, the levels of adrenaline and nor adrenaline will be lower that normal, This wi I result in vasoplegia by loss of the sympathetic vasotonus. The pituitary gland also produces antidiuretic hormone (ADYI), or vasopressin, which 35 acts on the kidneys in order to control the water resorption. ADH has a short half-life-time of about 15 minutes and a shortage of ADH will occur after some 60 minutes (with large individual variation s), Depletion of ADH- may result in diabetes insipidus, result% in 6 production of large quantities of urine in the order of several liters per hour. Unless replacement of fluid takes place, diabetes insipidus will result in hypovolernia.a murder reducton of blood pressure and eventual loss of circulation, resulting in ischenic damage of all organs, 5 Moreover, the pituitary gland produces adrenocorticotropic hormone (ACTM\ which staulates secretion of glucocorticoids which stimulates the synthesis of adrenaline and nors adremdine, la addition, the pituitarv gland produces thyroid-stimulating hormone (TSH), which stimulates the thyroid gland to secrete the hormones thyroxin (P) and triiodotyronine (T3> 10 Depletion of T4 and T3 may result in a change from aerobic to anaerobic metabolism in for example the heart, which may result in increased actate and pyruvate levels. Because the pituitary gland is dependent on the hypothalamus, the operation of the pituitary gland is reduced or ceases, resulting in decreased circulating levels of for example T3, T4, ADH, ACTH, cortisol and insulin, This results in impaired aerobic metabolism, 1$ increased anaerobic metabolism. depletion of hig-energy phosphates and increased lactate production, Side effects of high levels of atecholaminies are tachycardia, atrial and ventricular arrhythmias as well as conduction abncmafities. Pulmonary edema may result after high levels of catecholamines, especially 20 adrenaline Because of vasoconsrction caused by eatecholauines the organs may loose perfusion. Hypothalamus controls body temperature, and the failure of the hypothalamus may result in hvpothennia. 25 There are a number of different strategies suggested in the literature for maintaining organs after brain death, The fact that it is possible wh6'ith prolonged somatic support has been reported for a pregnant woman with brain death, By full ventilator and nutritional support, vasoactive drugs, maintenance of nonmothermia hormone replacerent and other supportive measures, the. fetus could be born several weeks after brain death of the mother, thereby 30 improving the s urvival prognosis for the fetus. A review article by Kenneth E. Wood and John McCartney entitled: "Management of the potential organ donor" published in Transplantation Reviews 21(2007), pages 204-218, and available online at wvwsciencedirect connsunmarizes the state of the art in this field. In Sweden, it is permitted to maintain the donor for 24 hours after brain death until 35 organ harvesting is performed After harvesting, the organs are examined for viability and stored, normally under hypothermia conditions unti transplantation.

7 Since ADH decreases rapidly, it is necessary to address this issue. Depletion of ADH sooner of later results in diabetes insiidu with high urifle volumes leading to hypovolemia. Tbis has been counteracted by infusion of large volumes of colloidal or crystalloid fluid, such as Ringer' solution. Another approach is to add a vasopressor agent, such as arginine 5 vasopressin, desmopressin, DDAVP or Minirin. The decrease of thyroid hormone level should also be addressed in order not to aggravate metabolism Thus, addition of T4 and/or T3 may be appropriate. The reduction in ACTH and cortisol may be addressed by giving methylprednisolone, or a similar agent. 10 In order to maintain proper perfusion of the organs, especially the kidney, it is considered that a mean arterial pressure MAP of at least 60 mmHg should be upheld, see ftor example the above-mentioned review article. This may be done by adding ctechoamines such as nor-adrenaline and/or adrenaline However, there is evidence that addition of adrenaline and/or nor-adrenaline may aggravate the conditions for some organs, amd there is a 1.5 tendency in the art to avoid the addition of catecholamines Traditionally, dopamine has been the inotrope of choice in doses titrated to ensure cardiac output and vasoconstricion to ensure perfusion pressure gradients to the myocardium and the renal circulation. Catechoiamninies have a alf-life of approximately a few minutes when circulating in blood, Normal secretion in the adrenal medulla of adrenaline is 0,2 pgktgmin and of nor 20 adrenaline 0.05 prg/kg/min, It is reported in the literature that administration of nor-adrenaline has been associated with myocardial damage and initial nonfunctioning after cardiac transplantation It is hypothesized that the "catecholamine stomi" after brain death may cause myocardial ischemia or rapid desensitization of the beta-adrenergc signaling pa hway Administration of 25 further nor-adrenalne after brain death may further desensitize the myocardial beta-adrenergic signaling, Another possible explanation might be that, under massive catecholamine release, the uptake and inactivation metallization systems may be saturated, resulting in a down regulation of beta adrenergic cardiac receptors (BAR) Le. a reduction of BAR density, which 30 may be dose dependent The recovery potential of BAR remains unknown, but may have an impact on organ function. In addition, catecholamines vnay sulfocnjugate, which is regarded as an inactivation process by which the organism "pools" free plasnma catecholamines into inactivated derivates, which subsequently are deconjutaged and released. 35 Thus, there is evidence that high levels of catecholamines may impair the alfa- and/or beta-receptors potency, In addition, the elimination system may be saturated, which may finally result in poor graft outcome.

8 A fundamental idea of the present embodiments is to replace at least some of the substances and/or hormones that are no longer excreted, or are excreted in substantially lower levels, by the brain dead body compared to a living body, The focus is to maintain hemodynamic stability by cardiovascular support because it may maintain all of the donor 5 organs in the best possible condition. The inventor has found that adrenaline and nor-adrenaline are two substances that would be beneficial to add, but the addition of either of the substances is controversial and may result in undesired side effects as mentioned above. Although the exact mechanism is unknown today, it is believed that a high level of 10 catecholamines, such as under the catecholaminee storm" will cause a depletion of the stores of catecholamine normally found in the nerve terminals and adrenal medulla. in addition, the vascular tonus is lost, because the nerve tenaninals receive no signals from the brain, Nor-adrenaline is normally produced in the pre-synaptic nerve terminal from tyrosine, which is an amino acid present all over the body in large quantities. 15 Fig. I is a schematic and simplified view showing a nerve terminal of the sympathetic nerve system, The nerve terminal ends in a presynapti c adrenergic Varicosity i I having a cell membrane 12, A postsynaptic effector cell membrane 14 is positioned a short distance from the cell membrane 12. The distance is called the synaptic cleft and may be about 20 nm in a chemkal synapse, 20 Tyrosine is transported into the varicosity I I via a transporter 15 and. into the cytoplasma, wherein the tyrosine is cowetted to DOPA under the influence of an enzyme; Tyrosine Hydroxylase (TH). This step is considered to be the ratedimiting step in the synthesis of nor-adrenaline and adrenaline. DOPA is transformed to dopamine in the cytoplasma under the influence of an 25 enzyme; Aromatic L-amino acid decarboxylase (AAADC), Dopamine is taken up into vesicles 16 via an active transporter 17 called VMA T-2 (Vesicular Monoamine Transporter), which is relatively non-specific and can transport different catecholanines, such as nor-adrenaline and dopamine, and other substances. Only about 50% of the dopamine produced is normally transported into the vehicles 16; the rest is 30 metabolized by an enzyme called MAO (Monoamine Oxidase), see further below. There are a great number of vehicles in the nerve terminal Inside the vehicle, there is an enzyme; Dopamine-p-hydroxylase (DvH), which converts the dopamine entering the vesicle nto nor-adrenaline (NA). in addition, any nor adrenaline present inside the varicosity 1I is transported into the vehicle 16 by the same 35 transporter 17 VMA' -2, In this way, nor-adrenaline is reused. A portion of the nor-adrenaline inside the varicosity does not enter the vesicle 16 but is metabolized by the enzyme MAO, 9 Thus, there is a competition between the enzyme MAO and the active transporter 17 VMAT 2, both wih regard to dopamine and nor-adrenaline The concentration of nor-adrenaline inside the vesicle is very high A Concentration in the range of 1 mole/liter has been reported, 5 At depolarization of the nerve cell membrane at the arrival of a stimulation signal, several voltage dependent calcimi ion channels 18 allow the passage of calcium ions through the varicosity membrane 12. Elevated levels of calcium ions promote the fusion of vesicular membrane with the membrane of the varcosity witl subsequent exOeytosis of nor-adrenaline NA, The fusion process involves the interaction of specialized proteins associated with the 10 vesicular membrane (VAMPs, vesicle-associatd membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associed proteins). When the vesiele emnits its content into the synaptic cleft, the nor-adrenaline passes into the synaptic cleft and may interact with afa- and beta-receptors present at the effector cell membrane, as showni by arrows in Fig. 1. Since the concentration of nor-adrenaline in the vesicle is extremely high and because the 15 concentration of nor-adrenaline in the synaptic cleft normally is very low, and because the distance across the synaptic cleft is very small, some 20 nm, the nor-adrenaline will more or less explode due to the high conentration gnaient and rapidly reaches the receptors at the effector cell membrane. The entire process comprising receipt of a depolarization voltage, inflow of calcium and exocytosis of nor-adrenaline takes often less than 1/1I:h of a second, 20 The released nor-adrenaline may also interact with presynaptic receptors of alfa-2 type and beta-type, The alfa-2-receptor may influence directly on the vesicle and diminish the release of nor-adrenaline, The beta-receptor may facilitate the release of nor-adrenaline, The mechanism is not clearly understood for such direct influence of the release of the nor adrenaline. 25 After some time, nor-adrenaline attached to the receptors is released froml the receptors in the synaptic cleft. The nor-adrenalne present in the synaptic cleft is transported into the adrenal varicosity by an active transporter 19, called NET (nor-opinephine transporter, nor-epinephrine = nor-adrenaline), This transporter has a high affinity for nor adrenaline. NET removes free nor-adrenaline fron the synaptic cleft, often within 0.1 seconds 30 However, a small portion of the free nor-adrenaline in the synaptic cleft passes out to the surrounding interstitial fluid and subsequently to the blood circulation. Circulating nor adrenalin>e is rapidly metabolized in the liver, normally within a few minutes, Thus, most of the nor-adrenaline released during exocytosis is reused, A portion is lost to the circulation and a portion is lost inside the adrenergic varicosity due to 35 metabolization by MAO before entering the vesicle 16, Such lost nor-adrenaline is replaced by newly produced nor-adrenaline from tyrosine as explained above, 10 There is a negptiv feed-hack regulation of the synthesis of nor-adrenaline from tyrosine. Thus, a high concentration ofnor-adrenaline at the presynaptic alf&~2-receptors seems to decrease the production of nor-adrenaline, probably via interference with the rate limiting enzyme TH, The distance fom the synaptic cleft to the blood circulation may be about 0 mm to several millimeters and is thus very much larger than the synaptic cleft Thus, it takes long tme for nor-adrenaline to diffuse fmm the synaptic cIef to the blood circulation and vice versa. Consequently, the blood concentration of nor-adrenaline in a living human body is normally low, In addition, it takes a high concentration in the blood in order for some nor 1 adrenaline to diffuse to the synaptc cleft and influence upon the receptors of the effector cell membrane. Adrenaline is produced from nor-adrenaline by an extra enzymatically driven step in the adrenal medulla The enzyme s called phenvlethanolamine N-methyltransferase (PINMT) and converts nor-adrenaline to adrenaline This enzyme is present essentially only in the IS adrenal medulla, The adrenal medulla comprises nerve tenninals siiniar to the adrenergic varicosity shown in Fig. I but lacks a postsynaptic portion, Instead, the exocytosis takes place directly into the blood stream Normally, the adrenal medulla excretes about 80% adrenaline and 20% nor-adrenaline into the blood. The above description is vaid fbr a living body such as the human being. When thle 20 body becomes brain dead, this condition is preceded by a catecholanine storm as explained above. Thus, as much nor-adrenaline as possible is released by exocytosis in the sympathetic nerve system, causing increase of the vascular system resistance by means of the alfa receptors of the effector cells. Consequently, all vesicles 16 in the nerve trminal are emptied into the synaptic cleft, Possibly the uptake mechanism of the NET transporter 19 is 25 overloaded and the concentration of nor-adrenaline in the synapti cleft will increase, probably by a factor above 100, This will cause a disturbance of the reuse of nor-adrenaline and the reuse of the vesicles after exocytosis. In addition, there will be a down-reguiation of the release of the vesicles by the alfa-2-receptors, Furthermore, the new production of nor adrenaline will be down-regulated by the high synaptic concentration of nor-adrenaline, Most 30 of the produced nor-adrenaline will pass out into the blood circulation and be metabolized by the liver. Consequently, all stores ofnor-adrenaiine in the nerve terminals will be used up and the operation of the nerve terminals will be severely disturbed, The adrenal medulla will also release all its storage ofadrenalme as well as nor adrenaline into the blood, The circulating catecholamines will be rapidly metabolized by the 35 livet Consequently, after the catecholamine storm, all stores of catecholamnines, particularly nor-adrenaline and adrenaline are exhausted There is only a small new production 11 of nor-adrenaline because the production from tyni.ne takes several hours to adjust itself to the new situation Thus, according to an embodiment of the present invention, adrenaline may be added in concentrations similar to those normally encountered in the blood The added adrenaline > interacts with beta-receptors to promote for example cardiac output. Adrenaline has numerous other actions in the body as is well known to the skilled person, According to another embodiment, nor-adrenaline may be added in concentrations sufficient to cause diffusion front the blood to the synaptic cleft and to the receptors present therein. normally atla-receptors, in order to interact with for example alfareceptors to cause 10 vasoeonstriction, Nor-adrenaline has numerous other actions in the body as is well known to the skilled person, Howevernor-adrenaline is normally produced and normally acts at sites ditferenr from the blood, This means that nor-adrenaline in the blood circolation may have a fast and direct effect at certain locations of the body,for example the kidney, while it may take longer 15 time and have less effect at other locations, for example the vascular system Thus, the consequence of adding nor-adrenaline to the blood circulation is very complex and incongruous. One mechanism which may decrease the action of the nor-adrenalin circulating in the blood and diffusing to the synaptic deft, may he the fact that any noradrenaline reaching the 20 synaptic cleft will be rapidly taken up by the NET transporter and he entered into the presynaptic nerve terminaL. Since the nerve termina is depleted of nomradrenaline. this action will be fast Thus the NET transporter wil compete with the activation) of the effector cell receptors and decrease the action of the added circulating nor-adrenaline In order to obtain an effect a high concentration of nornadrenaline in the blood wiH be required which is 25 incompatible with other operations in the body. If nor-adrenaline is added to the blood circulation, nor-adrenaline will be absorbed or soaked up by the nerve teninals Thus the state of depletion of the nerve terminals after the catecholamine storm may be reversed and normal operaton of the nerve terminals may be resumed Howevr, because the brain dead body does not emit any nerve signals, the cakhun 30 channels remain unstimulated and no exocytosis and release of nor-adrenaline may take place. The inventor has Iund that the addition of cocaine tog ether with norvadrenaline would permit the use of much lower levels of nor-adrenaline in the blood ciretlation and still obtain the desire defects of vasoconstriction.One h pothess for explaining this result may be that the cocaine acts as NET inhibitor, which is previously known. By blocking the reuptake 35 of the nor-adrenaline from the synaptic cleft, the NET transporter will no longer compete with the alfa-receptor and the nor-adrenaline diffusing from the blood to the synaptic cleft may cause the desired action. Other explanations may be relevant in combination.

12 In order to test this hypothesis, other NET inhibitors were tested, such as desipramine and imipramine, w which both are known to be NET inhibitors, It was shown that similar results were obtained by these ticyclic antidepressants, However, cocaine has a much smaller half life time of about I hour while imipramine has a half life time of 12 hours and desipramine 5 has a half-ife time of 30 hours, It was also shown that Venafaxine (half-life time of S hours) had a similar effect, Thus, it seems that NET1' inhibition is at least desirable in order to potentiate the effect of blood circulation nor-adrenaline. The conclusion is that a combination of NET inhibitors and nor-adrenaline would produce a synergetic effect in a brain dead, respirated body, in order to maintain or increase 10 the vascular resistance and potentiate the effect of blood circulating nor-adrenaline, At least a combination f nor-adrenaline and tricyclic antidepressants (including cocaine) would have the synergistic effect, The same substances also have influence upon the action of adrenaline in the brain dead., respirated body, A hypothesis is that the tricycl antidepressants have similar effect on 1$ beta-receptors as has cocaine, for example to prevent down regulation of beta adrenergic cardiac recep ors (BAR), ie. a reduction of BAR density, see above. Typical NFT inhibitors are the following substances; Tertiary Arne Tricyclics, such as: Amitriptyline (ELAVIL), Clomipranine (ANAFRANIL), Doxepin (ADAPIN, SINEQUAN> I nipramine (TROFANIL), Trvimipranine 20 (SURMONTIL); Secondary Amine Tricyclies, such as; Amoxapine (ASENDIN); Desipranmin (NORPRAIMN); Maprotinile (LUDIOMIL); Nortriptyline (PAMELOR); Protriptyline (VIVACTIL); Venlafaxin (EFFEXOR); Atomexetine (WELLB UTRIN); Duloxetine 2$ (CY MBALT A); Mirtacapine (REMERON); Norclomiprarn-ine; Oxaprotiline; Lofepramine, Reboxerine, Maprotiline, Nomifcnsine. Doxepin, Mianserin Vitoxazine; Mirtazapine, Nifsoxetine and cocaine, The potency seems to be highest for Desipramine, Protriptylin and Norclomipramine, In one embodiment, cocaine (benzoylmethyl ecgonine) has been used. Cocaine acts 30 as a NET inhibitor of nor-adrenaline and dopamine. The neuronal terminals will be protected from the high svstemic levels of catecholamines. The level of eatecholamines in the circulating blood may be maintained by infusion of small amounts if adrenaline and/or nor adrenaline, Thus, the neuronal action will be preserved in spite of exposure for high levels of circulating catecholamines both during the "storm" and subsequently during the next 24 hours 35 before harvesting of the organs, By the addition of adrenaline and/or nor-adrenaline, the sympathetic and parasyrpathetic tones may be maintained, preventing for example uncontrolled vasodilatation and tachycardia, 13 Cocaine and NET inhibitors may also or ahemadvely act via further mechanisms not known today, and may have a beneficial effect ftr preserving organs before harvesting in a brain dead, respirated body, Cocaine analogues may operate in the same way. Analogues may be any analogue as 5 defined above. It is believed that it is the stimulant effect of cocaine that is active, Thus, cocaine analogues mean cocaine analogues with stimulating effect, Cocaine-analogues with both stimulant & local anesthetic effects are: Dimethocaine or arocaine (DMC) ((3-diethylamino-dimethylpropyl)-4-aminobenzoate); and 3-(p Fluorobenzoyl)tropane ((I 5S)-~ethyb8azabicyclo[3,2 1]ocan-yl)4-fuorobenzoate), 10 Cocain-analogues for stimulant effects with local anesthetic efkcts removed are; CIT (methyl (I R,2S8.3,58)-3-(4~Iodophenyl)~8-.methy1 -8-azabkcyco(3.2f]octane-2> carboxylate); f-CPPIT' (3-Chlorophenyl)-2p(3'phenylisoxazol-5y-vtropane); FE-p CPPIT (N42'-uhoroethy1)-3p~(tchorophenyl)-2p-(3-phenylisoxazol-Sylnortropane); FP 4-CPPHT (N-(3-Fluoropropyl)-3 g-(4 t chlorophenyl)-2pr(3'-phenylisoxazo i5tyl)nortropane); 15 Altropane (methyl (1 R,2S,3S,5S)-3-(4-fluoropheny?)-84((E)-3-iodoprop-2-enyl]-8 azabicyclo[3.21 octane-2-carboxylate); Brasofensine ((E)- (1 R,2R,33,5)3-(3,4 dichkorophenyl)- methl--aabcclo[j3.21 ]oct-2-yl]-N-mrethoxymethanimiine); CFT' (methyl (IR2S,3S,5S)-3-(441uorophenyl)-8-methyb 8-azabicyclo[j3,2.1]octane-2 carboxylate); Dichloropane (methyl ( tR2S,3S,5S)-3-(3,-ydichorophenyl)- 20 azabicyclo3 ,2,1 joctane-2-carboxylate); Diluoropine (methyl (IS S,5R)-3-bi4 fluorophenyi)methoxy-8-methy-8-aabicyclo[j3.2J I octane~2 -carboxylate); iotflupane (*l) (methyl (1IR,2S,3StS-3-4-odpheny'l)-8-34uoropropyl)-8-azabicyclo(32llae2 carboxylate); Nocaine (methyl (3R,4S)44-chlorophenl-i-methpiperidine3 carboxylate); Tesofensine ((It 2R3,5S)-3-(3,4.-dichlirophenyl)-2-(ethoxymethy1)~8-methy 25 8-azabicyclo(3,2. I]octante); Troparil (methyl (R,2S,3S,5S)8-methyl-3-phenyl -8 azabicyco[3,2.]oclane-2-carbxylate); Tripixane (methyl (IR,28,3. SS)-3-(3,4 dichloropheny1)-8-oxabicyclo{3..11]ocwane-2~carboxylate); (-)-Methyl-l-methyb4pi-(2 naphthy }piperidine-3i-carboxylate (methyl (3S,48)-I -methy b4-naphthale-2-ylpipcridine-3 carboxylate); PIT (2-.Propanoyl-3-(4-isopropylphenyl)-tropane); PTT (2-ropanoyi-4p-( 4 30 tolyl)-tropane); RT- 121, LPCIT (propan-2-y? (1R,2S,3S)3(4iodophenyi) '8-methyl-8 azabicyco[3.2,1 joetane-2-carboxylate); RiT-126 ((1R,28,3S,5S)-8-methy 2-1,2,4 oxadiazol-S-methyl)- phenyh-8-aabicyclo[3.2. 1]ctane); RT 150 (cyclobuty ( R,28,3 S,5S)-8-methy 3-( 4-methylpheny;-8-azabicyco[3.2.]octatne-2-carboxylate); RT 336 (R,2S,3S,5S)- 8-methyc 2-(3-(4-methyipheny)isoxao~-y)-3~(4-chophenyl)-8 35 azabicyclo[l3,2 ]octane); WF-23 (20-Propanoyl-3f-(2-naphth y)-tropane); WF-33 (2a (Propanoyl)-3p-(2-(6-methoxynaphthyli)-tropane).

14 The use of a cocaine analogue with the stimulating effect removed and including a local anesthetic effect cannot be used for the purpose of the present embodiments. Lidocaine is a typical example. However, infision of Lidocaine will result in vasodilatation and a lowering of the blood pressure, It is expected that other loc anesthetic agents similar to 5 Lidocaine will produce the same blood pressure lowering effect, It has been found that by using a NET inhibitor, such as cocaine or a cocaine analogue (stimulating) r a tricyclic antidepressant, it is possible to maintain a brain-dead, heart-beating, respirated donor for 24 hours, with substantial maintenance of organ viability, by intravenous ejection of the NET inhibitor and nor-adrenaline, 10 In particular, the heart will benefit by the NET inhibitor, which seems to decrease the cardiac irritability, In addition, it has been found that puimnonary edema may decrease by the use of a NET inhibitor, This wil improve the result of subsequent pulmonary transplantation, By further addition of small amounts of a vasopressor agent, the operation of the 15 kidney can be maintained and the outcome of kidney transplamation is expected to improve, The same is true for the liver and other organs, such as pancreas, intestines, etc. This may be caused by the improved cardiovascular stability obtained, The body is provided with proper respiratory ventilation -to keep the partial pressures of oxygen and carbon dioxide at suitable levels. Normally the brain dead body has no 20 spontaneous respiration, which means that active ventilation is required, Such ventilation may take place in any manner previously known, for example by a respirator, by extemal compression of thorax, by manual or mechanical means, etc, The body is also provided with an infusion solution ftr maintaining fluid balance. The kidneys produce urine at a desired output level of at least I 0 m1kg/hour. Thus, a fluid, 25 such as Kreb's Ringer's solution, is infbsed at a rate of about I to 5 m/kg/hour to comnpensate for kidney output, sweat and fluid losses during respiration. The composition may further contain additional components such as cortisone, thyroxin (T4), insulin, triiodotyronine (T3, a vasopressor agent, such as arginine vasopressin, desmopressin or inirin, and methylprednisolone (cortisone). 30 In order to avoid diabetes insipidus, it may be proper to add desmopressin already as early as possible, for example a bolus at the start of the intervention and then a normal continuous do"se as produced by the body. Desmopressin may be titrated in depen&nce of the urine output, in order to maintain the goal of for example .0 mI/kg/hour. Since the urine output immediately after the catechounine storm is very small or even non-existent, it may be 35 required to add a Diuretic agent, such as Furosemide (LASIX) in order to start urine production, 15 In one example the composition comprises the NET inhibitor, such as cocaine, and in addition adrenaline, nor-adrenaline cortisonethyroxin, triiodotyronine, and desmopressin, The ratio between the NET inhibitor:nor-adrenaline may be about 1 1, in some embodiments, the adrenaline and/or nor-adrenaline may be partly or entirely 5 replaced by an equivalent substance, For example, phenylephrine is an alfa- I -agonist and may replace nor-adrenal ine, It seen that phenylephrine is about 5 times ess potent as nor adrenaline, Dopamine may be added in quantities less than about 0.01 mgikg/min The embodiments also relate to an infusion solution comprising the composition as 10 defined above dissolved in a pharmaceutical acceptable medium. Examples of acceptable mediums are physiological sodium chloride solution, Hartmann's solution and Ringer's (acetate) solution, Since the added volume is very smal; in the range of 1L .n our =0.04 m/kg/hour), the ingredients may be dissolved in sterile non-ionic water ie. pure H2O2 The final amounts of the different components, which may be present in the inkfsion 15 solution of a volume of 50 ml, are about 0. 1 to about 10 mg of noradrenaline for example I mg, 0.1 to about 10 ng of adrenaline, such as I mg, 0.I to about 10 mng of the NT inhibitor, such as I mg The other components, which may be present, may be in an amount of about 0.05 to about 3 mg of triiodotyronine T3, about 100 to about 1000 mg hydrocortisone, insulin and desmopressin 20 EXPERIMENT I The following ingredients: Om ( ml) adrenaline, I mg (1 ml) nor-adrenaline, 0.3 mg (3 ml) T3, 300 mg (3 ml) cortisone, 36 mng (9 ml) Minirin and I mg (3 mi) cocaine were dissolved in 50 ml physiological sodium chloride solution. The solution was added to the 25 brain-dead, hean-beating cadaver of a pig with a weight of 40 kg, by intravenous infusion at an initial rate of 17 m/hour, which was subsequently decreased in a dose dependent manner in order to maintain the mean arterial pressure MAP above about 60 mmig. The infusion rate could be reduced to about 0.4 ml/hour over 24 hours, In order to maintain blood volume, Macrodcx replacement fluid was added at 100 30 ml/hour (2,5 mlkg/hour) to support a urine output of about 9 liters over 24 hours. The rest of the added fluid is removed from the body via lung respiration and sweat. In order to counteract any tendency to form edema or any vascular instability, i may be proper to add dextran to the replacement fluid, such as Dextran 40 or Dextran 70. For reducing the risk of diabetes insipidus, a bohas of 12 mg Minirin was given at the 35 start of the treatment. The cadaver showed no significant signs of organ dysfunction, The heart, lungs, liver, kidney, and other organs were proper for transplantation purpose, 16 The blood pressure in an experiment with the above solution at a pig with a weight of 40 kg is shown in Fig, 1 The upper curve is the systo ic pressure, the middle curve is the calculated mean arterial pressure MAP and the lower curve is the diastolic pressure The ordinata shows the blood pressure in mnHg and the abseissa shows the time in horse. 5 After 14 hours, the infusion rate was increased resulting in a clear and immediate increase of blood pressure, The infusion rate was then lowered to obtain baseline pressures, As is shown in Fig, 1, the MAP was maintained at 80 nmtig, which is sufficient fr keeping all organs well perfused of blood. During the harvesting of the organs after 24 hours, the infusion of the solution was 10 again increased to baseline of L7 mbour during halfan hour before harvesting aid maintained until all organs were removed, An infusion rate of 1 'nilmnhour corresponds to an infusion of 0,015 pg/kg/min of adrenaline and nor-adrenaline, which is less than the normal production rate of the adrenal medulla which may be about 0,5 g(/kg/min such small infuinon rate into the blood is i5 believed to be tolerated by the organs and the system of the brain dead body, EXPERI MEN 2 A similar experiment was conducted wherein cocaine was replaced by desipamine 3 mg of desipramine was added instead of I mg cocaine to 50 ml of physiology ical sodium 20 chloride solution, in addition I mg of adrenaline and I mg of nor-adrenaline was included in the solution, The deslpramine solution was added to a pig similar to the pig in Experiment I at time instance 21 hours. The infusion rate was 1,7 mihour. The infusion rate was increased to 3,2 mi/our at vimne instance 22 hours and the blood pressure started to rise .At time instarnce 25 26 hours, the infusion rate was decreased to 2,5 m/our. At time instance 28 hours, the infusion rate was decreased to 1,7 mI/hour, The blood pressure during the time interval from 17 hours to 35 hours is shown in Fig, 3, In the same way as Fig. 2, the upper curve is the systolic blood pressure, the middle curve is the calculated mean arterial pressure MAP and the low 'er curve is the distolic 30 pressure. In addition, the mean pulmonary pressure is shown at the bottom curve. As can be seen, the brain-dead body answered on the infusion of desipramine by increasing the blood pressure from a mean pressure of about 40 mmlIg to a mean pressure of 80 mnHg. When the infusion rate was decreased, the blood pressure went down to about 60 mmi-fg, but never decreased further, It is believed that desipranmine maintained its NET 35 inhibitory effect over a long time because of its long hatf-life time. Thus, desipramine was active even when the infusion of desipramine was decreased and for several hours thereafter.

17 EXPERIMENT 3 A similar experiment was conducted wherein cocaine was replaced by imipramine. In this experiment, adrenaline and nor-adrenanne was added at a constant rate of 0.4 mi/hour At time instance 21 hours, a bolus of 2 mg cocaine was added and resulted in an increase of the $ blood pressure. The effect of the bolus of cocaine ceased after about 3 hours and a bolus of imipramnine was added at time instance 24,5 hours. The o us of inipramine resulted in an increase of blood pressure from about 80 mmnUg to about 100 mnng. This is shown in the diagram of Fig. 4,which however is blurred by the fact that the pressure measurement tubes were clotted and need to be flushed. 10 The infusion solution comprising the substances mentioned above is added to the blood circulation intravenously. The addition takes place by means of an electronically conrnoled infusion pump as shown in Fig. 5, Fig 5 shows an infusion kit according to an embodiment, The kit comprises a bag 21 for maintaining the inftusion solution The bag may comprise a volae of 50 ml of infusion 15 solution A tube 22 connects the bottom of the bag 21 w it an infusion pump 23, which may be a syringe pro ided with an electric motor for automatic operation, A peristaftic pump operating on the tube 22 may aiteratively be used, A second tube 24 connects the pump with a needle 25 intended to be introduce into a vein of a brain-dead, heart beating, tespirated potential donor. A rtea v any ty pe. of access or connection to the vascular system may be 20 used such as a venous catheter Since hie volume to be infused over several hours is only about 50 ml, a large syringe may replace the bag and the pump, In another embodiment, the volume of infusion solution is about 100 ml, which will be sufficient for a large patient of up to 100 kg during 24 hours, In this case, the entire procedure may take place fully automatically, without ary need for manual intervention. 25 Fig 6 discloses several infusion bags 31 41 , 61, 7 1 and 8 , The bags are the same as the <orresponding bag 21 of ig. 5, Six bags are shown in Fig. 6, but there may be any nu m b er of bags as required A tube 32, 42 52, 62 2, 82 connects the bottom of the bag with aninfusion pump 33,4353 6373, 83 which may be a syringe or a peristaltic pump, A second tube 34, 44, 54, 64, 74, 84 connects the pump with a needle 35 intended to be 30 introduced into a vein of a brain dead, heart-beating, respirated potential donor, A common tube 36 connects each end of the second tube to the needle 35. Each bag may comprise one or several of the ingredients mentioned above For example, bag 31 may comprise adrenaline, bag 41 may comprise nor-adrenaline, bag 51 may comprise cocaine or a NET inhibitor, bag 61 may comprise Minirin, bag 71 may comprise a 35 mixture of hormones, such as 13, T4, cortisone, etc, and bag 81 may comprise an infusion solution such as Kreb-Ringer solution, which is an sotonic infusion solution comprising glucose.

18 Each pump may be controlled by a computer 90 as shown in Fig, 6, The computer receives input signals from sensors 91, 92, 93 etc, For example pump 33 may be controlled in dependence of the cardiac output, for controlling addition of adrenaline, pump 43 may be controlled in dependence of the blood pressure or vascular resistance for controlling the 5 addition of nor-adrenaline, pump 53 may be controned in dependence of the effect of adrenaline and/or nor-adrenaline or may be controlled according to a desired predetennined control strategy, pump 63 may be controlled in dependence of the the urine output, pump 73 may be controlled according to a desired control strategy and pump 83 may be controlled for balancing the fluid loss via urine, sweat and respiration. 10 The computer may operate according to several strategies. One strategy may be to add cocaine at a rate which is proportional to the addition rate of nor-adrenaline. Another strategy may be to add cocaine in proportion to the addition rate of adrenaline or the sun of adrenaline and A further strategy would be to add cocaine in a constant rate independent of the addition of adrenaline and/or nor-adrenaline, 15 If another NET inhibitor is used having a long half-life, abolus at the start of the intervention would be adequate, followed by a smaller bolus after six hours etc, The effect of the bolus will be present during a long time after the bolus injection and the hemodynamic stability can be controlled by small amounts of adrenaline and nor-adrenaline, The treatment or intervention should start as soon as possible after determination of 20 brain death, There may be time delays between the actual death and the time when the condition of brain death is determined and such time delays should be as short as possible. The treatment may start with a bolus injection, especially if there is a substantial time delay and the blood pressure alread is below about 50 rnmHg, The treatment is continued as until it is determined that organ harvesting should be 25 performed, Shortly before harvesting, the infusion is i creased to prepare the organs for maintaining as proper condition as possible during harvesting and the time immediately following harvesting. The treatment is performed fror immediately after brain death until organ harvesting. The inventor has performed more than 20 experiments with pigs and using cocaine in 30 combination with adrenaline and nor-adrenaline. in each case it has been possible to maintain the blood. pressure at a constant level of fir example 70 mmH g from the initiation of the intervention and over 24 hours. Ususally, the dose required during the first hours has to be reduced, for example from 13L mL/hour during the first six hours and down to 0,4 m/hour during the last six hours. However, there are large individual differences. By this action, the 35 blood pressure immediately after the catecholamnine storm can be maimained at a sufficient level, thereby avoiding a blood pressure below 40 mmlg, which nornially occurs after the catecholamine storm if no intervention is performed 19 In many cases, it is not required to control all parameters and use six (or more) individually controlled supplies. One versatile combination would be to have adrenaine and cocaine in bag 31 ,noriadrenaline and cocaine in bag 4 1,Minirin in bag 51. infusion solution in bag 61 and the other ingredients in bag 1, and excluding bag 8 1 A further embodinent would indude adnaline nor-adrenaline and cocaine in bag 31, further ingredients in a second bag 41 and infusion solution in a third bag 51, Alternatively, both the infusion solution, which comprises a NET inhibitor. and the replacement fluid may be arranged in the same bag whicb in this case should have a volume of about 25 liter, 10 In the claims the termcomprises/comprisng" does not exclude the presence of otter cements or steps Furtherrnore, although individuals hsed a plurality of means, elements or method steps may be implemented by e-g a single uit. Additional, although individual features may be included in different claims or embodiments, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a 15 combination of features is not feasible and/or advantageous. In addition singular rerences do not exclude a plurality. The terms "a", "an "irst" "second" etc do not preclude a plurality. Reference signs in the claims are provided merely as a cdarifying example and shall not be construed as limiting the scope of the claims in any way. Although the present invention has been described above with reference to specific 20 embodiment and experiments it is not intended to be limned to the specific f'rm set forth herein. Rather, the nvention is limited only by the accompanying claims and, other embodiments than those specified above are equally possible within the scope of these appended claims

Claims (20)

1. A composition for intravascular administration for treatment of a brain-dead, heart-beating, respirated potential organ donor for maintaining hemodynamic stability, comprising: adrenaline, nor-adrenaline and a NET inhibitor. 5

2. The composition according to claim 1, wherein the NET inhibitor is a stimulating analogue of cocaine.

3. The composition according to claim 1, wherein the NET inhibitor is at least one tricyclic antidepressant included in the group comprising: Amitriptyline (ELAVIL); Clomipramine (ANAFRANIL); Doxepin (ADAPIN, SINEQUAN); Imipramine (TROFANIL); Trimipramine 10 (SURMONTIL); Amoxapine (ASENDIN); Desipramine (NORPRAMIN); Maprotinile (LUDIOMIL); Nortriptyline (PAMELOR); and Protriptyline (VIVACTIL).

4. The composition according to claim 2, wherein the NET inhibitor is at least one agent included in the group comprising: beta-CIT; beta-CPPIT; FE-beta-CPPIT ; FP-beta-CPPIT ; Altropane; Brasofensine; CFT; Dichloropane; Difluoropine; loflupane; Nocaine; Tesofensine; 15 Troparil; Tropoxane; PIT; PTT; RTI-121, IPCIT; RTI-126; RTI-150; RT1336; WF-23; WF-33.

5. The composition according to claim 1, wherein the NET inhibitor is at least one agent included in the group comprising: Venlafaxin (EFFEXOR); Atomexetine (WELLBUTRIN); Duloxetine (CYMBALTA); Mirtacapine (REMERON); Norclomipramine; Oxaprotiline; Lofepramine; Reboxetine; Maprotiline; Nomifensine; Doxepin; Mianserin; Viloxazine; Mirtazapine; 20 and Nisoxetine.

6. The composition according to claim 3, wherein the NET inhibitor is desipramine.

7. The composition according to claim 3, wherein the NET inhibitor is imipramine.

8. The composition according to any one of the previous claims, wherein the NET inhibitor is present in an amount of 0.2 to 5 times of the amount of nor-adrenaline. 25

9. The composition according to claim 1, wherein a ratio between the NET inhibitor, adrenaline and noradrenaline is 1:1:1.

10. The composition according to any one of the previous claims, further comprising at least one of: hydrocortisone, thyroxin, insulin, triiodotyronine, dopamine, desmopressin, and methylprednisolone. - 21

11. An infusion solution comprising the composition according to any one of the previous claims dissolved in a pharmaceutically acceptable medium.

12. The infusion solution according to claim 11, wherein the pharmaceutically acceptable medium is pure water, Ringer's acetate solution or physiological sodium chloride solution. 5

13. The infusion solution according claim 11 or 12, wherein said composition is dissolved in the pharmaceutically acceptable medium in an amount of 1 mg of adrenaline, 1 mg of noradrenaline, and 1 mg of NET inhibitor in 50 ml of fluid.

14. A kit when used to intravenously administer a composition to treat a brain-dead, heart beating, respirated potential organ donor, comprising: 10 an infusion bag comprising an infusion solution comprising a composition according to any one of claims 1 to 10; an infusion pump for pumping the infusion solution to a needle inserted into a vascular system of the donor for controlling an amount of infusion solution entered into the donor vascular system; and 15 tubing for interconnecting the bag, pump and needle.

15. Use of adrenaline, noradrenaline and a NET inhibitor in the preparation of an infusion solution for maintaining hemodynamic stability by infusing the solution according to claim 11, 12 or 13 into the circulation system of a brain-dead, heart-beating, respirated potential organ donor, comprising: 20 determining that the donor is brain dead; continuing or initating respiration of the donor for oxygenation; wherein the infusion solution is for infusion into the circulation system of the donor.

16. The use according to claim 15, wherein a volume of 50 ml of the infusion solution comprises 1 mg of noradrenaline and 1 mg of adrenaline and 1 mg of NET inhibitor. 25

17. The use according to claim 15 or 16, wherein the infusion solution further comprises at least one of: hydrocortisone, thyroxin, insulin, triiodotyronine, dopamine, desmopressin, and methylprednisolone. - 22

18. A method of maintaining hemodynamic stability of a brain-dead, heart-beating, respirated potential organ donor comprising the step of determining that the donor is brain dead; continuing or initating respiration of the donor for oxygenation; and 5 infusing into the circulation system of said potential organ donor the infusion solution according to claim 11, 12 or 13.

19. The method according to claim 18, wherein a volume of 50 ml of the infusion solution comprises 1 mg of noradrenaline and 1 mg of adrenaline and 1 mg of NET inhibitor.

20. The method according to claim 18 or 19, wherein the infusion solution further comprises at 10 least one of: hydrocortisone, thyroxin, insulin, triiodotyronine, dopamine, desmopressin, and methylprednisolone.