Cardioplegic solution

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US007270833B2

(12) United States Patent

Steen

(io) Patent No.: (45) Date of Patent:

US 7,270,833 B2 Sep.18, 2007

(54) CARDIOPLEGIC SOLUTION

(75) Inventor: Stig Steen, Lund (SE)

(73) Assignee: Jolife AB, Lund (SE)

( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 441 days.

(21) Appl. No.: 10/344,038

(22) PCT Filed: Aug. 7, 2001

(86) PCT No.: PCT/SE01/01719

§ 371 (c)(1),

(2), (4) Date: Jul. 21, 2003

(87) PCT Pub. No.: WO02/11741 PCT Pub. Date: Feb. 14, 2002

(65) Prior Publication Data

US 2004/0018245 Al Jan. 29, 2004

Related U.S. Application Data

(60) Provisional application No. 60/230,812, filed on Sep. 7, 2000.

OTHER PUBLICATIONS

"Conversion of Postischemic Ventricular Fibrilation With
Intraaortic Infusion of Potassium Chloride," Eivind Ovrum et al,
Ann Thorac Surg, vol. 60, No. 1, 1995.

19th Congress of the Scandinavian Society of Anaesthesiologists in
Linkoping, Ssweden, Jun. 29-Jul. 3, 1987, "Acta Anaesthesiologica
Scandinavia," Supplementum 86, vol. 31, 1987, L. Bjella et al,
"Potassium Chloride Used to Prevent Ventricular Fibrillation at
ReperfUsion in Open Heart Surgery," No. 11.
Heart, vol. 80, No. 4, 1998, D.A. Chamberlain, "Antiarrhythmic
Drugs in Resuscitation".

The Canadian Journal of Surgery, vol. 23, No. 2, Mar. 1980, A.
Addetia et al, "Perfusion in Cardioplegia: an Experimental Study".
Anaesfhesiol Reanimat, vol. 18, No. 6, 1993, Von H. Wulf et al,
"Kaliumsubstitution bei koronarchirgischen Eingriffen: K+-Mg++-
Aspartat-Komplex (Inzolen) versus Kaliumchlotid,".
The American Journal of Cardiology, vol. 33, No. 1, Jan. 1974, John
C Fischer et al, "Studies on Ventricular Defibrillation".
File WPI, Derwent Accession No. 1996-096008, Novos Blood
Circulation Pathology Inst, "Protecting Myocardium in Heart
Operation-with Perfusion-free Hypothermia by Introduction of
Cooled Cardioplegic Soln.Contg. Potassium".
File WPI, Derwent Accession No. 2000-557077, Blood Circulation
Pathology Res Inst, "Method of Prophylaxis Heart Rhythm Disor-
der in Cardiosurgery Operations".

Susan Budavari et al, "The Merck Index, eleventh edition," 1989, Merk & Co., Inc., p. 1211-1213, No. 7580, 7586, 7599, 7601; p. 1216, No. 7647.

* cited by examiner

Primary Examiner—David M. Naff

Assistant Examiner—Deborah K. Ware

(74) Attorney, Agent, or Firm—Browdy and Neimark,

PLLC

1

CARDIOPLEGIC SOLUTION

The present application claims priority from, inter alia, the provisional U.S. application 60/230,812 filed Sep. 7, 2000. 5

FIELD OF THE INVENTION

The present invention relates to use of potassium ions for the production of a medicament for the prevention of stone io 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. 15

This application is a 371 of PCT/SE01/01719 filed Aug. 7, 2001.

BACKGROUND ART

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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, 25 is the reason for acute death. Most of these deaths occur outside hospitals. Before 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 30 muscle cells become more and more inefficient which results in an increase 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 35 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 40 are irreversibly disrupted. If such a condition occurs during cardiopulmonary resuscitation, it is not possible to perform 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 45 clinical result of cardiopulmonary resuscitation as it is practiced 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 50 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 cardiopulmo- 55 nary 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 60 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, 65 and the patient is intubated and ventilated with 100% oxygen. It is also very difficult to transport a patient having

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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 directly 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