CARDIOPLEGIC SOLUTION

Abstract: Use of potassium for the production of a cardioplegic solution for the prevention of stone heart development during acute cardiac ventricular fibrillation in connection with cardiopulmonary resuscitation is described, as well as a cardioplegic solution comprising potassium and a method for the prevention of stone heart developement during acute cardiac ventricular fibrillation in connection wiht cardiopulmonary resuscitation.

Description: CARDIOPLEGIC SOLUTION Field of the Invention The present invention relates to use of potassium ions for the production of a medicament for the prevention of stone heart development during acute cardiac ventricular fibrillation in connection with cardiopulmonary resuscitation (CPR) , to a cardioplegic solution comprising potassium and to a method for the prevention of stone heart development during acute cardiac ventricular fibrillation. The present application claims priority from, inter alia, the provisional U.S. application 60/230,812. Background art In the Western world 30 % of all deaths is due to ischemic heart disease, i.e. coronary atherosclerosis. In about 70 % of these deaths acute ventricular fibrillation causes the circulatory arrest. In about 30 % of these deaths electromechanical dissociation, i.e. heart arrest without ventricular fibrillation, is the reason for acute death. Most of these deaths occur outside hospitals. Be- fore effective cardiopulmonary resuscitation can be initiated several minutes without any form of cardiac massage often occur. When the heart does not receive blood and energy, the ionic pumps of the heart muscle cells become more and more inefficient which results in an in- crease of the intracellular concentration of calcium. When the intracellular concentration of calcium increases, the contractile state of the heart increases. Ultimately, a condition described as "stone heart" or ischemic contraction of the heart occurs; Cooley described in 1972 an ischemic contraction condition of the heart and called it "stone heart" . He described the heart in these cases as small and irreversibly contracted, and it appeared to be literally frozen in systole, as certain protein structures of the heart muscle cells are irre- versibly disrupted. If such a condition occurs during cardiopulmonary resuscitation, it is not possible to per- form effective external or internal heart massage, because there will be no lumen left in the ventricles and therefore no possibility for the blood to pass through the heart. The clinical result of cardiopulmonary resus- citation as it is practised today for patients dying outside hospital is very poor, with a mortality of around 97 - 98 %. In most cases, it is not possible to perform effective heart massage 20 minutes after the cardiac arrest, and in some countries there is a recommendation that if you can not bring the heart to work within 20 minutes, you may declare the patient dead and stop all types of cardiopulmonary resuscitation. When a patient's heart today stops outside a hospital the general population has been trained in doing car- diopulmonary resuscitation. This consists of mouth to mouth blowing in of expiratory air and manual compression of the chest, i.e. 5 compressions of the chest, followed by 1 inblow of expiratory air or 2 inblows and 15 chest compressions. A cardiac output of about 10-15 % of the normal output in rest may be obtained by manual external chest compression, and this low output is not enough to give the heart enough blood to survive more than for a few minutes. If especially well trained personnel arrive to the accident place, defibrillation of the heart is tried if ventricular fibrillation is diagnosed, and the patient is intubated and ventilated with 100 % oxygen. It is also very difficult to transport a patient having circulatory arrest into hospital because it is not possible to perform effective external chest compression during transportation in the ambulance. For that reason most of these patients are declared dead if they not can be saved on the accident place. Thus, there is a great world-wide need to develop methods and means for treatment of such patients also under transport until access to adequate artificial circulation means at hospitals or other medical centres . Object of the invention The object of the present invention is to eliminate the above-mentioned current drawbacks and shortcomings in connection with treatment of acute cardiac ventricular fibrillation during CPR and thereby, save lives or organs for transplantation. This object is achieved by use of potassium ions for the production of a cardioplegic solution as defined by way of introduction in a method for the prevention of stone heart development during acute cardiac ventricular fibrillation, said use and method having the features ... defined in the appended independent claims. The present invention also refers to a kit for cardiopulmonary resuscitation comprising said cardioplegic solution. Further advantages and other features appear from the description and the appended subclaims. Description of the Drawing (s) Fig 1 illustrates the effect of CPR with potassium chloride and V-A ECMO on the aortic pressure during an experiment with pigs. Fig 2 illustrates the effect of CPR with potassium chloride and V-A ECMO on the potassium ion concentration in aortic blood. Summary of the Invention Thus, the active ingredient in the cardioplegic solution according to one aspect of the present invention is potassium, more precisely potassium ions. The concentration of potassium depends on whether the cardioplegic solution is to be injected directly into the heart or administered as an infusion, e.g. via a vein catheter. The potassium ion concentration reaching the heart, i.e. the coronary vessels, must be 12-30 mM, preferably 16-22 mM, with a view to switching off the electric activity of the heart, thereby avoiding the undesired stone heart condition and allowing heart compressions. By making the heart muscle cardioplegic, i.e. relaxed, the wall tension of the heart is lowered to near zero, and coronary perfusion will be obtained at much lower coronary perfusion pressures. Thus, in the case when the cardioplegic solution initially is to be injected direct- ly as a booster into the heart, the potassium ion concentration in the cardioplegic solution must be 12-30 mM, preferably 16-22 mM, and most preferably approximately 20 mM, i.e. no dilution effects occur. After the initial booster injection, i.e. after approximately 10-60 s, normally 30 s, the cardioplegic solution according to the present invention should be administered continuously as a maintenance dose to the heart, e.g. as an infusion at the injection site. The potassium ion concentration reaching the heart during the continuos administration must also be 12-30 mM, preferably 16-22 mM. In the case when the cardioplegic solution is to be initially administered as an infusion solution, the potassium ion concentration normally is 12-140 mM due to the dilution effect in the aortic blood on the way to the heart. Further, after the initial infusion having a high potassium ion concentration, the cardioplegic solution should be continuously administered in the form of an infusion, i.e. after approximately 30 s, followed by incremental decreases of the potassium ion concentration, while main- taining the potassium ion concentration in aortic blood between 15 and 20 mM. The expression "injected directly into the heart" as used throughout the patent application text means that the cardioplegic solution is injected directly in the coronary vessels, e.g. the coronary arteries or sinus coronarius . Due to a slight dilution effect the potassium ion concentration of the cardioplegic solution should be a bit higher than 12-30 mM when injected directly into the left ventricle. No or negligible dilution effects occur when injected directly in the coronay vessels. In some circumstances a potassium ion concentration of up to 140 mM is applicable, but in such a case high amounts of vasodilator has to be present to compensate for the vasoconstrictive effects. When administrated as an "infusion solution" on the venous side, the best results are obtained if the cardio- plegic solution is administered via a central venous catheter into the right atrium, the right ventricle or arteria pulmonaris. Peripherally induced infusion is less applicable. It should also be noted that a lower temperature of the cardioplegic solution generally requires a lower potassium ion concentration to obtain adequate cardio- plegia . When the cardioplegic solution according to the present invention is administered as an infusion, the potas- sium ion concentration is initially high, if the infusion is given into the patient on the venous side. Thereafter, the potassium ion concentration is incrementally decreased due to a saturation effect in the blood, in which a potassium ion concentration of 15-20 mM is desired to be continuously maintained. Said concentration normally varies between 12 and 140 mM dependent on such factors as the administration flow rate, e.g. depending on the infusion pumps used; the total blood volume of the patient and the amount and type of vaso- dilator administrated. Thus, the initial potassium ion concentration and the continuous decrease thereof during the infusion treatment is established by the practitioner dependent on the factors mentioned above. The cardioplegic solution according to the present invention also contains a vasodilator, i.e. a blood vessel expanding agent, due to the undesired vasoconstrictive effect obtained by the administration of potassium to the heart. Non-limiting examples of the vasodilator are papaverin, magnesium, nitroglycerin, nifedipin, and nitroprusside . The most preferred vasodilator is papaverin. The concentration of the vasodilator depends on the vasodilator used, and is preferably papaverin in an amount of 40-120 mg. A combination of two or more of the above-mentioned vasodilators may also be used. Alternatively, the vaso- dilator may be present in a solution to be separately administered, however at the same time or somewhat in advance, in relation to the potassium containing cardioplegic solution. Further, the cardioplegic solution according to the present invention also contains one or more physiologically acceptable and compatible components, e.g. anions originating from the potassium salt which is dissolved _ during the preparation of the cardioplegic solution. Non- limiting examples of anions are chloride, acetate, lac- tate, phosphate, carbonate, and bicarbonate. A combination of two or more types of anions may be present in the cardioplegic solution. Preferably, chloride ions are present in the cardioplegic solution, i.e. potassium chloride is initially dissolved during the preparation. Other ' physiologically acceptable components may also be present. Bicarbonate ions also have a buffering action. If the above-mentioned lower potassium ion concentration limits would be further lowered, no satisfactory cardioplegic effects would be attained. If the above-mentioned upper concentration would be exceeded, vasoconstriction problems might occur if not an adequate dosis of papaverin or another vasodilator is administered simultaneously. The pharmaceutically acceptable medium, in which the components described above are present, is preferably water. The cardioplegic solution according to the present invention is conveniently commercialised and stored in the form of a solution in a container, preferably plastic bags or bottles. E.g., depending on whether the cardioplegic solution is to be used as an injection booster solution, an infusion booster solution, or as a continu- ously administrated solution after the initial injection or infusion, the potassium ion concentration may be predetermined and the container be labelled with the potassium ion concentration in question. Alternatively, one standard potassium ion concentration of the cardioplegic solution is used, and the concentration thereof reaching the heart is regulated by the administration flow rate. In another embodiment the present invention refers to a kit containing the cardioplegic solution in a convenient container or more than one container optionally having different labels depending on the potassium ion concentration to be used. Further, the kit may contain equipment normally used for injection and/or infusion, e.g. needles, cannulas, catheters, etc. Alternatively, the potassium containing solution and the vasodilator containing solution may comprise different components of the kit and be present in ' different containers, however intended to be used simultaneously or essentially simultaneously. In one aspect the present invention also relates to the use of potassium for the production of a cardioplegic solution for the prevention of stone heart development during acute cardiac ventricular fibrillation in connec- tion with cardiopulmonary resuscitation, wherein potassium in the form of a salt with one or more kinds of anions is dissolved in a pharmaceutically acceptable medium, optionally together with a vasodilator, wherein the potassium ion concentration is 12-30 mM in the case when the cardioplegic solution is to be initially injected as a booster directly into the heart, and 12-140 mM in the case when the cardioplegic solution is to be initially administered as a infusion. It has not been known before to use potassium ions for the prevention of the fatal stone heart condition during CPR treatment of acute cardiac ventricular fibrillation. Even though it is previously known to admin- ister potassium, e.g. potassium chloride, during intentional cardioplegia in connection with open heart surgery, such as heart transplantations and coronary bypass surgery, wherein the purpose of the potassium administra- tion only is to keep the heart non-beating without damage during the operation phase, the present inventor has surprisingly found, after long term studies, that the addition of potassium to the heart during CPR of experimental animal suffering from acute ventricular fibrilla- tion eliminates the development of stone heart, thereby making it possible to recover all hearts even after one hour of heart massage. Successful prolonged heart massage has previously not been possible, inter alia due to lack of reliable CPR devices at the accident place and during the transport to hospitals. Also, the present invention is paradoxal and goes against the common sense, i.e. that the heart electricity first is practically abolished or "killed" with a view to revive it thereafter. Thus, the present invention is applicable at the location for the acute cardiac ventricular fibrillation and during the transport of the patient to a hospital . Further, the combined use of a heart-lung machine is not required before arrival at the hospital. Instead, it suffices with the combined use of an effective heart compression device, as exemplified below ("Lucas") . In still another aspect the present invention relates to a method for the prevention of stone heart development during acute cardiac ventricular fibrillation, wherein a cardioplegic solution as defined above is administrated to the patient as a booster solution via direct injection into the heart, more precisely the coronary vessels, or in the left ventricle, or via intravenous infusion, each followed by a continuous administration of the potassium containing cardioplegic solu- tion, in the latter case while maintaining the potassium ion concentration in the patient's aortic blood between 15 and 20 mM during a sufficient time period with a view to preventing development of stone heart and allowing compressions of the heart during the CPR. In such a way several lives can be saved. Optionally, the method according to the present invention also provides a possi- bility to maintain the circulation in the body of a patient the life of which later on may turn out to be impossible to save. By maintaining the circulation and thereby the blood supply to the organs in the body, these organs might be a subject for transplantation, thereby saving the lives of other patients. This aspect might be applicable in the future when or if persons in advance decide to make their organs after death available for transplantation. In accordance with one embodiment of the method ac- cording to the present invention, the potassium ion concentration in the heart after the administration of the cardioplegic solution may be normalised or reduced towards normal levels by the administration of insulin and glucose in the form of an infusion solution, whereby the potassium ion concentration is reduced towards a normal level. This administration is also beneficial for the reconditioning of the heart. Normally the amount of insulin and glucose added is approximately 100 international units of short term acting insulin and 10 ml 30% or 50% glucose, respectively, and the solution thereof is infused to the heart during a convenient time period, normally about 10-60 s, preferably about 30 s. According to the prevailing guidelines defibrilla- tion should be performed first in the treatment of ven- tricular fibrillation However, if possible, simultaneous chest compression should also be given. This is normally impossible in practice, mostly depending on that the patient becomes electrically conductive, thereby creating a risk for another person being in contact with the patient being defibrillated to be stricken with ventricular fibrillation. 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Ω 3 ii rr P μ- μ- rt rt μ> J TJ φ CQ P 3 o o LΠ X CQ < φ 0 Pi J TJ d J φ o rt Ωi tr J σi σi rt J μ- X μ- d O ti TJ rt P. φ LQ Ω Hi ^ Φ Ω CO PJ rt tr ϋ P o PJ CQ P rt 3 rt rt H rt φ ■ ; Φ P μ- PJ μ- μ- ii PJ tr D P rt μ- Φ Hi 3 rt CQ ii μ- Φ tr Φ i Ω tr rt Ω li tr P μ- Ω li μ- μ- Pi tr PJ tr 0 3 rt μ- tr rt Φ CD Φ tr LO φ PJ μ- 0 Φ μ- Pi ϋ rt P d P 0 Φ μ- d μ- Φ P μ- tr 3 PJ . ϋ 0 O Hi ii 3 O CO μ- μ- 0 Ω. rt Hi φ P PJ <! CQ PJ CQ P ti d CD Φ φ ti 3 d Hi CQ φ TJ P 0 0 l- 1 d PJ μ- • CQ Pi μ- d r μ- ii o\° μ- P ti LQ J Ω P tr CD Φ Φ rt t φ rt tr PJ 1 PJ rt φ -ti J P Φ Φ 0 Hi s: Φ o CQ 0 Φ • 0 0 P CQ CQ 1 J I 1 μ- CD Hi Hi P. 1 1 The idea then came up that if cardioplegia is induced to the heart during heart arrest, it would be possible to eliminate this stone heart condition and make 100 % of the hearts survive 60 minutes of heart compres- sion. In clinical heart surgery we routinely use potassium to accomplish depolarisation and cardioplegia. We induced ventricular fibrillation in pigs and then induced cardioplegia in the form of potassium chloride into a central venous needle or even directly into the left ven- tricle, thereby inducing cardioplegia. By a continuous infusion of potassium chloride we kept the heart in a cardioplegic condition. Then heart compressions for 1 hour were possible, without the development of stone heart. After 60 minutes we cannulated the pig in the femoral artery and vein and established an extracorporeal membrane oxygenation (ECMO) . Then, we washed away the potassium chloride by filtration, and the heart started to beat spontaneously again. When cardioplegia is induced in a heart at normotermia, 90 % of the need for oxygen is eliminated, and the heart is arrested in a relaxed condition. Such a heart is very easy to perform external or internal heart massage on. Potassium also creates vasoconstriction in the concentrations needed to obtain cardioplegia. This potassium induced vasoconstriction can be eliminated by vasodilators, e.g. by papaverine . By giving insulin and glucose it is also possible to reduce the potassium ion concentration. Administration of insulin and glucose are also beneficial for the reconditioning of the heart. An experiment performed is described in detail below. Internal cardiopulmonary resuscitation by continuous left ventricle infusion of potassium chloride The purpose of the experiment was to evaluate the effects of continuous potassium chloride infusion during internal CPR with a catheter inserted into the left ventricle and to investigate the need for ECMO (extracorpo- real membrane oxygenation) after high dose potassium chloride treatment during CPR, to obtain return of ROSC after prolonged CPR. The haemodynamic parameters continuously was meas- ured and stored as mean values every 5 second. Blood gases was analyzed with a Radiometer™ ABL 555 ® blood gas machine. Drug administration (Addex ® potassium 4mmol/ml, Fresenius Kabi, Uppsala, Sweden. 40mg/ml papaverin, NM Pharma, Stockholm, Sweden.) during CPR was given accord- ing a specific protocol. The test parameters were selected to meet the International Organization of Standardization (ISO) requirements for biological evaluation of medical devices (10993-4: 1992 (E) ) . The following data parameters were measured and stored as mean values every 5 seconds throughout the experiment : ECG, arterial pressure (SAP/MAP/DAP) , central venous pressure (CVP) , coronary perfusion pressure (CPP) , carotid flow (CF) , temperature, urine production (every 15 min), and blood gases. The blood gas (Radiometer™, ABL 555 ® ) data parameter were measured and stored intermittently or written down by hand throughout the experiment . Electrically ventricular fibrillation was induced electrically in healthy test pigs (25-80 kg in body weight) at normothermic conditions (a body temperature of 38 °C) . After 90 seconds of untreated ventricular fibrillation internal heart massage started manually and continued for 60 min. At the same time a booster injection of 10ml potassium (Addex ® potassium 4 mmol/ml, Fresenius Kabi, Uppsala, Sweden) and 3ml papaverin sulfate (Papaverin 40mg/ml, NM Pharma, Stockholm, Sweden) was given. Directly after a potassium infusion (Addex ® potassium 4 mmol/ml, Fresenius Kabi, Uppsala, Sweden) was started (100 ml/h for 20 min, 50 ml/h for 20 min, 20 ml/h for 20 min) . Thus, the potassium ion concentration of the aortic blood, i.e. the blood entering the heart, was kept at 15-20 mM, which is enough for maintaining cardioplegia. After 60 minutes of resuscitation V-A (venoarterial ECMO was established and by ultrafiltration the serum potassium ion concentration was reduced towards normal levels. The heart started to beat spontaneously when the serum (S) potassium ion concentration decreased to less than 8 mM. CPR in a 25 kg Swedish domestic pig After the 6-hour test period, the animal was put to death with a euthanasia solution. The heart was examined visually for signs of disease (ischemia, congenital defects, emboli or thrombosis) . As appears from Fig 1, which illustrates the time schedule for CPR with potassium chloride administration and A-V ECMO, the aortic pressure decreases during the CPR. After lh of CPR in combination with potassium administration, followed by ECMO, the heart rhythm of the pig was reinstated and ROSC came into effect. LΠ

Claims: CLAIMS 1. Use of potassium ions for the production of a cardioplegic solution for the prevention of stone heart development during acute cardiac ventricular fibrillation in connection with cardiopulmonary resuscitation. 2. Use according to claim 1, wherein potassium in the form of a salt with one or more anions chosen from the group comprising chloride, acetate, lactate, phosphate, carbonate, and bicarbonate, is dissolved in a pharmaceutically acceptable medium in a concentration of 12-30 mM in the case when the cardioplegic solution is to be injected as a booster solution directly into the heart, and in a concentration of 12-140 mM in the case when the cardioplegic solution is to be administered as an infusion solution, optionally together with a vasodilator. 3. Use according to claim 2, wherein the potassium ion concentration is 16-22 mM when the cardioplegic solution is to be injected as a booster solution directly into the heart . 4. Use according to claim 2 , wherein potassium chloride is dissolved. 5. Use according to claim 2, wherein the vasodilator is chosen from the group comprising papaverin, nifedipin, nitroglycerine, nitroprusside, and magnesium, preferably papaverin in an amount of 40-120 mg. 6. Use according to claim 2, wherein the pharmaceu- tically acceptable medium is water. 7. A cardioplegic solution for the prevention of stone heart development during acute cardiac ventricular fibrillation in connection with cardiopulmonary resuscitation, wherein it comprises potassium ions, and op- tionally a vasodilator, in a pharmaceutically acceptable medium, wherein the potassium has been dissolved in the medium in the form of a salt with one or more pharmaceu- LO LO NJ t μ> en o LΠ o LΠ o LΠ Ω <! O μ- ti J O P Ωi PJ μ- li H ^ Φ Ω < rt Φ CO μ- CO P φ <_I- φ CQ Ω •> rt μ- o 0 ii P μ- μ- P P rt rt o tr Φ rt tr H-> Φ Φ Hi tr rt Φ PJ < ϋ as rt P r ϋ 3 μ- o Ω ϋ Φ Φ • > TJ ti Hi Φ O Ω μ- Q O Φ s; Φ ^ rr tr tr ■• < Φ continuous administration of the cardioplegic solution; or infusion via a central venous catheter into the right atrium, the right ventricle or arteria pulmonaris, wherein the potassium ion concentration is continuously de- creased while maintaining the potassium ion concentration in the patient's aortic blood between 15 and 20 mM. 15. Method according to claim 14, wherein the potassium ion concentration when reaching the heart must be 12-30 mM, preferably 16-22 mM. 16. Method according to any of claims 13-15, wherein the potassium ion concentration of the heart is decreased after the end of the administration of the cardioplegic solution by infusion of a solution containing insulin and glucose . 17. Method according to any of claims 13-16, wherein the cardioplegic solution is administered to the patient during effective heart compressions.

Inventors: STEEN STIG, STEEN, STIG
Applicants: JOLIFE AB, STEEN STIG, STEEN, STIG
Application year: 2001
Main classification: A61K33
IPC codes: A01N1, A61K31, A61K33, A61K45, A61P9