WO1994007475A1

WO1994007475A1 - Perfusion of perfluorocarbon compound emulsion during percutaneous transluminal angioplasty

Info

Publication number: WO1994007475A1
Application number: PCT/US1993/008886
Authority: WO
Inventors: B. Mervyn Forman
Original assignee: Forman B Mervyn
Priority date: 1992-09-30
Filing date: 1993-09-23
Publication date: 1994-04-14

Abstract

A perfluorocarbon compound emulsion is administered before, during or after a procedure to reopen stenotic vessels to assure uninterrupted oxygenation to tissues distal to the stenosis.

Description

PERFUSION OF PERFLDOROCARBON COMPOUND EMULSION DURING PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY

This is a continuing application of Serial No.

07/953,221, filed September 30, 1992.

FIELD OF THE INVENTION

This invention relates to percutaneous transluminal angioplasty and more particularly to the perfusion of an oxygenated perfluorocarbon compound emulsion during prolonged angioplasty.

BACKGROUND OF THE INVENTION

Restricted blood flow to body tissues may be caused by a narrowing of arteries. This narrowing (or stenosis) may be caused by a number of factors, such

as atherosclerosis, thrombus formation or trauma. For example, atherosclerosis refers to the gradual deposition of fatty material, generally referred to as an atherosclerotic plaque, on the inside walls of arteries. A buildup of atherosclerotic plaque within an artery restricts the flow of blood through the artery. The body organ depending on the narrowed (stenotic) artery eventually reacts to the inadequate blood flow. The types of symptoms that are produced from inadequate blood flow vary, depending on which arteries in the body are narrowed. Percutaneous transluminal angioplasty is a procedure for reopening arteries narrowed by deposits of atherosclerotic plaque. Angioplasty may be used in numerous sites, such as with femoral, renal, cerebral and coronary arteries. In the procedure, a small guiding catheter is inserted into a vein and passed to the site of the narrowing or stenosis. A smaller balloon-tipped catheter is passed through the guiding catheter and positioned so that the balloon is within the stenotic region of the artery.

Once in position, the balloon is inflated to enlarge the inner diameter of the artery. In successful angioplasty, when the balloon is deflated, the stenosis of the artery is less severe, thus providing a patent artery which permits more blood to pass through the artery to the organ or tissue which was distal to the stenosis.

When the balloon is inflated, the blood flow to the tissue supplied by the artery distal to the balloon is cut off. Accordingly, the time that the balloon can be inflated is limited, particularly when the procedure involves organs which are extremely sensitive to the lack of oxygen, such as the brain or heart. During a single procedure the balloon may be inflated several times. However, even with multiple inflations, tissue elasticity and stenosis characteristics are such that a significant proportion of the treated patients experience restenosis of the treated artery within a few months. Prolonged inflation of the balloon may result in better resolution of the stenotic region. However, prolonged balloon inflation results in prolonged periods during which no oxygen is delivered to tissues distal to the balloon. That creates risk to the patient. For example, in percutaneous transluminal coronary angioplasty, prolonged balloon inflation results in myocardial ischemia, arrhythmias and eventually myocardial infarction.

Attempts to oxygenate tissue distal to the balloon to enable a longer period of balloon inflation have included perfusion of blood through the central lumen of the catheter. However, the passage of blood through the small diameter of the catheter lumen ' resulted in severe hemolysis.

SUMMARY OF THE INVENTION

It has been found that prolonged balloon inflation during angioplasty can be accomplished by passing an oxygenated perfluorocarbon compound emulsion into the artery through the lumen of the catheter.

Accordingly, the present invention comprises a method for enlarging a stenotic region of an artery by introducing a balloon catheter into the artery so that the balloon is positioned in the stenotic region. The balloon then is inflated one or more times to enlarge the inner diameter of the artery. During inflation of the balloon, an oxygenated perfluorocarbon compound emulsion is passed through the lumen of the catheter to supply oxygen to the portion of the artery distal to the inflated balloon. The flow rate of the perfluorocarbon compound emulsion through the catheter is sufficient to prevent significant ischemia, preferably being maintained within the range of from about 20 cc/min to about 150 cc/min. The number of balloon inflations at each stenotic site can vary and may range from one up to about ten or more as desired. Likewise, the duration of each inflation may vary, generally being within the range of from about 10 seconds to about 30 minutes.

Alternatively, to assure rapid infusion of the oxygenated perfluorocarbon compound emulsion to tissues, such as cardiac tissue, distal to the stenosis, the emulsion is passed through the burner of the guide catheter which is introduced into the vessel prior to the balloon catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

Those and other features and advantages of the present invention will be understood better by reference to the following detailed description, when considered in conjunction with the accompanying drawings wherein:

Fig. 1 is a schematic view of a patient showing the heart and main arteries involved in a percutaneous transluminal coronary angioplasty;

Fig. 2 is an enlarged schematic view of the heart showing the positioning of the guiding and balloon-tipped catheters within a coronary artery; and

Fig. 3 is an enlarged fragmentary cutaway view of the coronary artery and the balloon-tipped catheter. Fig. 4 is a graft depicting EKG abnormalities in crossover patients. Paired plots by patient are presented. In the figure, the number symbol (#) represents 0 time, normal EKG recorded throughout balloon inflation; the hollow circles represent a perfusion flow rate of 30 cc/min; the X's represent a perfusion flow rate of 60 cc/min; and the shaded area depicts that portion of the plot wherein Fluosol-PTCA demonstrates an advantage over Lactated-Ringer's PTCA.

Fig. 5 is a graft depicting the severity of anginal pain experienced during PTCA. Paired plots by patient are presented. The symbols are as set forth for Figure 4.

Fig. 6 depicts bar graphs relating to the trans-stenotic gradients of treated vessel. The Post

Prolonged treatment group includes Fluosol and Lactated-Ringer's PTCA.

DETAILED DESCRIPTION OF THE INVENTION

A preferred application of the present invention is in percutaneous transluminal coronary angioplasty. With reference to Figs. 1 to 3, such a procedure generally consists of introducing an introducer sheath 10 into the femoral artery 11 at the groin. A small guiding catheter 12 is inserted through the introducer sheath 10 and passed through the femoral artery 11 and dorsal aorta 13 and into the narrowed coronary artery 14 of the heart 16. A smaller balloon-tipped catheter 17 then is passed through the guiding catheter 12 and positioned so that the balloon 18 of the balloon-tipped catheter lies within the stenotic region of the artery 14.

The balloon-tipped catheter 17 comprises a pair of lumens 19 and 21. The first lumen 19 extends to the balloon 18 and is used for passing a fluid, preferably saline, to the balloon 18 to inflate the balloon and to pass fluid from the balloon 18 when the balloon is deflated.

The second lumen 21 extends through the balloon 18 to the distal tip 22 of the catheter 17. The second lumen 18 is open at the distal tip. The second lumen 18 is provided for passing an oxygenated perfluorocarbon emulsion through catheter 17 into the occluded portion of the artery 14 during balloon inflation.

The perfluorocarbon compound emulsion can be administered post-operatively, generally, no more than 6 hours after angioplasty and preferably no more than 4 hours after angioplasty. In a more preferred embodiment, the intracoronary infusion of the perfluorocarbon compound emulsion is begun as soon as possible following the angioplasty procedure, commonly during the reperfusion period. Infusion can occur by withdrawing the balloon catheter to a position proximal to the site of prior occlusion and passing the perfluorocarbon compound emulsion through the lumen of the balloon catheter, as described hereinabove. For example, emulsion administration can begin from about 5 to about 10 minutes after the onset of reperfusion.

However, as disclosed herein, it is preferable that the perfluorocarbon compound emulsion be passed through the balloon catheter during the angioplasty procedure, especially during and after inflation of the balloon when normal blood flow through the vessel is curtailed. In this manner, oxygenation of tissues distal to the balloon is not interrupted. An alternative mode of delivery is to infuse the perfluorocarbon emulsion through the lumen of a guide catheter. Essentially any one of a variety of commercially available catheters can be used so long as coronary angioplasty and infusion of an oxygen-transporting perfluorocarbon compound occurs either precedingly or coincidentally with the angioplasty procedure.

Administration of the emulsion can occur through both the guide and balloon catheters simultaneously or sequentially. The rate of flow can be adjusted to assure an appropriate infusion rate of emulsion.

As used herein, "perfluorocarbon compound emulsion" refers to an aqueous emulsion of an oxygen-transferable perfluorocarbon compound, preferably having a particle size of less than about 0.3 microns. Suitable emulsions have good oxygen transferability to ischemic, hypoxic and anoxic tissues, a favorable vapor pressure range to allow reasonable expiration of the perfluorocarbon compounds used in the emulsion and clinically acceptable toxicity. The emulsion may be transparent, translucent or opaque. The perfluorocarbon compound emulsion comprises at least one perfluorocarbon compound, an e ulsifier and physiological salts and monoglycerides thereof. Such perfluorocarbon compound emulsions are described in U.S. Patent Nos. 3,911,138 to Clark, Jr., 3,962,439 to Yokoyama et al. and 4,252,827 to Yokoyama et al., Yokoyama, K. et al.: "A Perfluoroche ical Emulsion as an Oxygen Carrier," Artificial Organs 8:34-40, 1984, and Yokoyama, D. et al.: "Selection of 53 PFC Substances for Better Stability of Emulsion and Improved Artificial Blood Substances", Advances in Blood Substitute Research. New York: Liss, Inc., 1983, all of which are incorporated herein by reference.

Preferred fluorocarbon compound emulsions comprise at least one perfluorocarbon compound having 9-11 carbon atoms selected from the group consisting of perfluorodecalin, perfluoromethyldecalin, perfluoro-alkylcyclohexanes having 3 to 5 carbon atoms in the alkyl, perfluoro-alkyltetrahydrofurans having 5 to 7 carbon atoms in the alkyl, perfluoroalkyltetrahydropyrans having 4 to 6 carbon atoms in the alkyl and perfluoroalkanes having 9 to 11 carbon atoms; at least one perfluoro-tert-amine having 9 to 11 carbon atoms selected from the group consisting of perfluoro-tert-alkylamines having 9 to 11 carbon atoms, perfluoro-N-alkylpiperidines having 4 to 6 carbon atoms in the alkyl and perfluoro-N-alkylmorpholines having 5 to 7 carbon atoms in the alkyl; a high-molecular-weight nonionic surfactant having a molecular weight of about 2,000 to 20,000; a phospholipid; and at least one fatty acid compound selected from the group consisting of fatty acids having 8 to 22 carbon atoms; and physiologically acceptable salts and monoglycerides thereof. The ratio of the perfluorocarbon compound and the perfluoro-tert-amine is 95-50 to 5-50 by weight.

The "high-molecular-weight nonionic surfactant" has a molecular weight of 2,000 to 20,000 and includes polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene alkyl ethers and polyoxyethylene alkyl aryl ethers. The concentration of the surfactant in the emulsion is about 2.0 to about 5.0%, preferably 3.0 to 3.5% (W/V) . The symbol "% (W/V) " means the amount proportion of a material by weight (gram) based on 100 ml of the resulting emulsion. Examples of the perfluorocarbons having 9 to 11 carbon atoms are a perfluorocycloalkane or perfluoroalkylcycloalkane which includes, for example, per f luoro-C₃.₅-alky lcyclohexanes such as p e r f l u o rome t hy l p ropy l cyc l oh a x a n e , p e r f l u o r o b u t y l c y c l o h e x a n e , p e r f l u o r o t r i m e t h y l c y c l o h e x a n e , perfluoroethylpropylcyclohexane, perfluorodecalin and p e r f l u o r o m e t h y l d e c a l i n ; a perf luoro-C₄.₆-alkyltetrahydropyran such as pe r f l uo roh exy l t et rahyd ropyra n ; a perf luoro-C₅.₇-alkyltetrahydrof uran such as p e r f l u o r o p e n t y l t e t r a h y d r o f u r a n , perf luorohexyl tetrahydro f uran and perfluoroheptyltetrahydrofuran; and a perfluoroalkane having 9-11 carbon atoms such as perfluorononane and perfluorodecane.

Examples of the perfluoro-tert-amine having 9 to 11 carbon atoms are a perfluoro-tert-alkylamine having 9 to 11 carbon atoms which includes, for example, per f luorotr i a l kyl a n i nes such a s perfluoro-N , N-dibutylmonomethylamine , pe r f l uo ro -N , N - d i ethy l penty l am i ne , p e r f l u o r o - N , N - d i e t h y l h e x y l a m i n e , per f 1 uo r o -N , N- d i p r opy 1 bu t y 1 am i ne and p e r f l u o r o t r i p r o p y l a m i n e ; a perfluoro-N ,N-dialkyl-cyclohexylamine having 9-11 c a r b o n a t o m s s u c h a s perfluoro-N, N-diethylcyclohexylamine; a perf luoro-N-C₄.₆-alky lpiper idine such as p e r f l u o r o - N - p e n t y l p i p e r i d i n e , p e r f l u o r o - N - h e x y l p i p e r i d i n e a n d perf luoro-N-butylpiperidine ; and a perf luoro-N-C₅.₇-alky lmorphol ine such as p e r f l u o r o - N - p e n t y l m o r p h o l i n e , p e r f l u o r o - N - h e xy l m o rp h o l i n e a n d perf luoro-N-hepty lmorphol ine . The ratio of the perfluorocarbon compound to the perfluoro-tert-amine to be used is 50-95 to 50-5 by weight and the total amount of perfluorocarbon compound and perfluoro-tert-amine contained in the emulsion is about 10 to about 50% (W/V) . The phospholipids used as emulsifier adjuvant in the invention are ones commonly used in the art, and those comprising yolk phospholipid or soybean phospholipid are preferable. The amount present in the emulsion ranges from about 0.1 to about 1.0% (W/V), and preferably about 0.4 to about 0.6% (W/V).

The fatty acid compound used as emulsifying adjuvant is a fatty acid having 8 to 22 carbon atoms, a physiologically acceptable salt thereof, such as sodium or potassium salt, or a monoglyceride thereof, which includes, for example, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid and arachidonic acid, and sodium or potassium salt and monoglyceride thereof. The fatty acid compounds may be used alone or as a mixture of two or more kinds thereof in such a minor amount of 0.004 to 0.1% (W/V), and preferably about 0.02 to 0.04% (W/V). Among the fatty acid compounds, the preferable ones are those having 14 to 20 carbon atoms and physiologically acceptable salts thereof, and the most preferable are potassium palmitate and potassium oleate, taking into consideration of the good solubility thereof and ease of preparing emulsions using the same.

An example of a perfluorochemical emulsion that can be used according to a method of the instant invention is Fluosol* (Green Cross Corporation, Osaka, Japan) , which is a sterile, isotonic perfluorochemical emulsion. The emulsion is stored frozen (-5*C to -30^#C) prior to use. Fluosol* is prepared from a perfluorochemical emulsion which contains perfluorodecalin in an amount of about 17.5% weight per volume; perfluorotri-n-propylamine in an amount of about 7.5% weight per volume; Poloxamer 188* in an amount of about 3.4% weight per volume; egg yolk phospholipids in an amount of about 0.5% weight per volume; potassium oleate in an amount of about 0.040% weight per volume; glycerol in an amount of about 1.0% weight per volume; and water as the remaining portion to make a total of about 100%. The average particle diameter of Fluosol* emulsified perfluorochemical particles as determined by a laser light scattering method is less than 270 nanometers.

P o l o x a m e r 1 8 8 ^® i s a polyoxyethylene-polyoxypropylene copolymer surfactant of about 8350 molecular weight. The structure of

Poloxamer 188* is:

HO-(CH₂CH₂0)_a-[CH(CH₃) (CH₂0) ]_b-(CH₂CH₂0)_C-H where values for a, b and c are approximately 74, 31 and 74, respectively. The structures of remaining constituents are well known.

Additional solution(s) can be added to the emulsion to dilute and to adjust pH, ionic strength and osmotic pressure. Examples of suitable additional solutions include the following solutions I and II, in combination to provide a final 20% emulsion:

ADDITIVE SOLUTION I

Component Amount f% w/v) Sodium Bicarbonate 3.5

Potassium Chloride 0.56

Water q.s.

ADDITIVE SOLUTION II

Component Amount (% (w/v)

Sodium Chloride 4.29 Dextrose 1.29

Magnesium Chloride 0.305

Calcium Chloride 0.254

Water q.s.

Fluosol* is prepared according to the manufacturer's suggested procedure. Briefly, about 20 minutes is required to thaw a bag of Fluosol* emulsion in a 37^*C water bath with the Fluosol* bag enclosed in a clear plastic bag. The additive solutions are stored at room temperature and are added sequentially with mixing, under aseptic conditions, to the Fluosol^® emulsion. The complete emulsion is mixed gently by inverting the bag 6 to 10 times.

Patients may be administered 100% oxygen (6 to 10 liters per minute) supplied through a non-rebreathing mask. Administration of 100% oxygen, when employed, can be initiated no later than the time the patient starts the Fluosol* infusion and continues for 8 hours. Prior to and following the requirement, oxygen may be administered at the discretion of the physician. Alternatively, the Fluosol* can be oxygenated, for example, with 95% 0₂/5% C0₂, to about 300-650 mm Hg partial pressure of oxygen prior to use. Furthermore, such an oxygenated perfluorochemical emulsion can be administered in conjunction with breathing of oxygen as aforementioned.

The balloon-tipped catheter can be of any design which comprises an inflatable balloon at the distal end and a lumen which extends through the balloon and is open at the distal tip of the catheter. Such catheters are commercially available. Presently preferred catheters include the Gruntzig Catheter manufactured by United states Catheter, Inc. and the Simpson-Robert Coronary Balloon Dilation Catheter manufactured by Advanced Cardiovascular Systems.

Once the balloon is positioned within the stenotic region of the artery, the balloon is inflated for a selected length of time, preferably from about 10 seconds to about 30 minutes for procedures involving percutaneous transluminal coronary angioplasty.

In the case of infusion before and during angioplasty, and in any event when the balloon is sited at the stenosis, emulsion can be passed through the lumen of the balloon catheter. For example, during inflation of the balloon 18, an oxygenated fluorocarbon compound emulsion is passed through the second lumen 21 of the catheter 17 and into the artery 14 distal to the occlusion. The introduction of the fluorocarbon compound emulsion into the artery may be commenced before, simultaneously with or after the inflation of the balloon. The fluorocarbon compound emulsion may be administered at temperatures, between ambient (25*C) or body temperature, (37'C) . The partial pressure of oxygen (p0₂) in the emulsion is typically maintained in the range of from about 300 mm Hg to about 650 mm Hg with p0₂'s in the upper portion of the range being preferred.

The rate at which the fluorocarbon compound emulsion is introduced into the artery will depend on the size of the artery being treated. The flow rate should be sufficient to prevent physiologically damaging ischemia. It is preferred that the flow rates be at least about 20 cc per minute. Lower flow rates are not preferred as the supply of oxygen to the occluded tissue may be insufficient. It is also preferred that the flow rate not exceed about 150 cc per minute. Greater flows are not preferred because high pressures are generated within the artery which may cause rupture. To minimize flow interruption during the procedure, it is preferred that the perfluorochemical compound emulsion be injected into the catheter from a large sterile reservoir, e.g., up to 1000 ml volume, which can be refilled during the procedure. The present invention is suited particularly to percutaneous transluminal coronary angioplasty procedures during coronary operations, e.g., to inflate a collapsed artery while supplying oxygen to the tissue cut off by the collapse. It also is applicable to opening blocked coronary arteries and to supplying oxygen to ischemic tissue during or following myocardial infarction. Thus, the instant invention relates to a method to reduce reperfusion injury, to control or to decrease infarct size and/or to improve ventricular function. The extent of reperfusion injury, infarct size and ventricular function are determinable practicing known techniques, such as those taught in Forman et al.: "Demonstration of Myocardial Reperfusion Injury in Humans: Results of a Pilot Study Utilizing Acute Coronary Angioplasty with Perfluorochemical in Anterior Myocardial Infarction", J. Am. Coll. cardiol. 18:911-918, 1991. A similar, and equally applicable application of the present invention is in retroperfusing oxygenated perfluorocarbon compound emulsion into coronary veins cut off from oxygen by occlusions in a coronary artery. In such an application, the balloon catheter is introduced into the coronary sinus. During diastole, the balloon is inflated and the oxygenated perfluorocarbon emulsion is retroperfused into the coronary veins. Inflation times are generally less than a second. The preceding description has been presented with reference to a presently preferred application of the inventions, i.e., percutaneous transluminal coronary angioplasty. It is apparent that the invention equally is applicable to other percutaneous transluminal angioplasty procedures, e.g., renal, femoral or carotid including interoperative procedures involving such arteries. It also is apparent that, depending on the specific procedure, the parameters of the procedure may vary. For example, for percutaneous transluminal angioplasty of arteries other than those serving the heart and brain, the preferred duration of each balloon inflation is at least about two minutes. For the carotid artery and other vessels serving the brain, it is believed that durations of from about ten seconds to about fifteen minutes can be used.

It also is apparent that, if desired, oxygenated perfluorocarbon compound emulsion can be administered through the guiding catheter or other catheters to supply oxygen to the tissue proximal to the inflated balloon. Additional perfluorocarbon compound emulsions may be administered through peripheral I.V. lines, if desired. The present invention offers the advantages that prolonged balloon inflation times now can be practiced without resultant physiologically damaging ischemia. Moreover, the present invention enables the angioplasty procedure to be performed on multiple sites within a single vessel or in multiple vessels, again without resultant ischemia.

Various aspects of the instant invention are set forth in the following non-limiting examples.

EXAMPLE I

Twelve adult mongrel dogs, weighing 20 to 30 kg, were anesthetized with pentobarbital, 25 mg/kg I.V., and, after intubation, were placed on a Harvard volume respirator. An electrocardiogram was monitored and recorded continuously throughout the study. Bilateral carotid artery cutdowns were performed and a #8 French Millar end-tip manometer catheter was advanced to the left ventricle under fluoroscopic control for continuous monitoring of pressure and dp/dt. A #10 French guiding catheter was advanced to the ostium of the left coronary artery under fluoroscopy and a 3.0 mm balloon catheter (either the USCI Gruntzig catheter or the ACS Simpson-Robert catheter) was passed, coaxially through the guiding catheter, into the circumflex branch. In one dog, the balloon catheter was placed in the left anterior descending branch (dog #7) . Heparin, 5000 units, was given i.v. in each dog. No anti-arrhythmic drugs were given to any dog at any time.

Fluosol-DA^_ 20% was oxygenated by bubbling oxygen through a tube into the solution for 30 minutes. In this manner, a p0₂ 600 mm Hg was achieved. When 100% oxygen was passed over Fluosol-DA 20% in a vented bottle while the solution was slowly swirling, similar oxygenation (600 mm Hg) was obtainable. The infusion of Fluosol-DA 20% through the central lumen of the balloon catheter was initiated before balloon inflation and after recording the baseline ECG, LV pressure and dp/dt at 50 mm/sec paper speed. A low flow roller pump was used to deliver the Fluosol-DA 20%. The flow rate, which had been measured before insertion of the balloon catheter, was

-^Fluosol-DA 20% is a perfluorocarbon compound emulsion manufactured by the Green Cross Corporation of Osaka, Japan. determined again. If the flow rate was satisfactory, the balloon then was inflated; if not, the flow was adjusted to the desired level before balloon inflation. Inflation of the balloon was performed with contrast medium, so that the inflation could be followed fluoroscopically. Contrast medium was injected into a proximal portion of the left main coronary artery through the guiding catheter, after balloon inflation, to confirm that the inflation resulted in complete occlusion of the branch to the antegrade flow of blood.

The ECG, LV pressure and dp/dt were recorded periodically at 50 mm/sec paper speed during the infusion and, in the majority of the dogs, during the 15 to 30 minute period following the completion of the Fluosol-DA 20% perfusion. A postmortem examination of the heart was performed at the end of each study by sectioning the myocardium at 1 cm intervals and by making a longitudinal incision along the length of all major branches of the coronary arteries.

Dogs were perfused with Fluosol-DA 20% at flow rates ranging from 5 to 30 ml/min while balloon inflation times ranged from 8 to 53 minutes. No dog in the Fluosol-DA 20% group died prematurely, i.e., before completion of the Fluosol-DA 20% perfusion and post-perfusion periods of observation had ended. The baseline data was obtained after approximately 15 to 45 seconds of balloon occlusion with no infusion of any oxygenated material through the distal port of the catheter.

Perfusion with Fluosol-DA 20% was inadequate in Dog #3 (only 5 cc/min) , since Silastic tubing was used in the roller pump. That tubing collapses excessively with movement of the roller pump head so that a higher flow rate could not be achieved in that dog. ST segment depression on the ECG occurred while no hemodyna ic or post-mortem changes were noted. With the use of Tygon tubing in the other 11 dogs, any desired flow rate was achieved easily.

In Dog #7, the balloon catheter could not be placed in the circumflex branch and therefore was placed in the left anterior descending branch. The latter had numerous large side branches (diagonal and septal perforators) , four or five of which were obstructed by the inflated balloon. The branches, which were proximal to the tip of the balloon catheter, could not receive Fluosol-DA 20% and it was not surprising, therefore, that hemorrhage in the distribution of the branches (the septum) was found. Marked ST-T wave changes on the ECG occurred within seconds of balloon inflation, while systemic pressure fell to 75 mm Hg. Of interest in the study was the observation that the frequency of baseline PVC's, 6.8% of the normal beats, decreased to 4.3% during Fluosol infusion and increased markedly in the post-infusion period to 19.8%. In Dog #12, the balloon catheter was advanced quite far distally, due to the large size of the circumflex artery in the dog, and balloon inflation resulted in obstruction of a moderate sized branch. Elevation of the ST segment on the ECG occurred within several minutes and, on postmortem examination, a small area of hemorrhage over the epicardium only (no intramural changes were seen) was noted in the region corresponding to the obstructed branch. There were no hemodynamic effects of that occlusion and no arrhythmias occurred.

In the remaining nine dogs, there were.no EKG changes, no arrhythmias, no adverse hemodynamic effects and no abnormal postmortem pathology demonstrable either during or after myocardial perfusion with Fluosol-DA 20%.

EXAMPLE II

An additional control animal was investigated in which oxygenated saline (P0₂ greater than 600 mm Hg) was passed through the distal part of the catheter. In that animal the procedure was carried out exactly as in dogs 8 through 12 of Example I , but oxygenated saline was infused at 60 ml/min into the coronary artery. The dog developed ventricular fibrillation and died within two minutes. EXAMPLE III

A second animal also was prepared similar to dogs 8 though 12 of Example I. That animal received a predose of methylprednisolone (10 mg/kg) at 24 hours and 10 minutes pre-infusion. The animal received (30 ml/min) Fluosol-DA 20% for eight minutes. No abnormalities were observed, but after a 15 minute recovery period the procedure was aborted.

EXAMPLE IV

Thirty-one human patients were randomized into Fluosol-DA 20% (F-DA) treated (n=14) and control (n=17) groups prior to elective percutaneous transluminal coronary angioplasty (PTCA) , which was performed initially in all patients in a routine manner. In the F-DA group, following steroid premedication and a 0.5cc i.v. test dose, i.e. F-DA was infused at 0.5cc/sec x 1 min. before and during balloon inflation if routine PTCA had been performed without difficulty (n=10) . In response to PTCA, the two groups did not differ clinically, angiographically, hemodynamically or by serial ECG'S. RA, PA and PA wedge pressures each increased slightly in both groups immediately following PTCA (P<.05) , but the changes were not different between groups. Coagulation profiles, blood chemistries and CBC's before and one day after PTCA did not differ between groups, except for a greater WBC rise in the F-DA group (P<.01), which likely resulted from the steroid medication.

EXAMPLE V

In a cross-over study involving twenty-five human patients, each patient was treated with a routine (single inflation) PTCA procedure and then randomized to receive additional PTCA procedures using perfusion with oxygenated Fluosol-DA 20% (F-DA) and then oxygenated lactated Ringer's solution or the reverse. Electrocardiograms (EKG) (abnormalities in EKG values are indicators of physiological ischemia) were obtained for each patient during each procedure and the duration of any EKG abnormalities were assessed for each portion of the study. In 18 of the 25 patients, the duration of EKG abnormalities was significantly longer (P< 0.05) during lactated Ringer's PTCA than during F-DA-PTCA as shown in Figure 4.

The EKG abnormalities lasted 15.5 ± 9.7 seconds longer during lactated Ringer's-PTCA than during F-DA PTCA. The difference is suppressed due to early termination of lactated Ringer's-PTCA procedure in 8 patients after marked EKG changes and/or anginal pain was experienced by the patient. EXAMPLE VI

The severity of anginal pain (a measure of physiological ischemia) experienced during each phase of the PTCA procedure described above in Example V also was assessed. The results are shown in Figure 5.

The severity of anginal pain was scored on a ten point scale with zero equal to no pain and nine representing unbearable pain. Of the 25 patients, 11 patients had pain of the same score with either prolonged dilatation procedure. Twelve patients had less severe pain with F-DA-PTCA than with lactated

Ringer's-PTCA. The mean difference in severity pain scores was 1.7. Pain experienced during F-DA-PTCA was significantly (p=0.002) less than during_, lactated

Ringer•s-PTCA.

Although the duration of the pain was similar, the time to onset and the severity of pain were significantly improved with F-DA-PTCA as a prolonged dilatation procedure compared to lactated

Ringer's-PTCA.

EXAMPLE VII

The stenotic gradients of the treated vessels also were assessed. The results are shown in Figure 6. The stenotic gradient is the pressure on the proximal side of the stenotic lesion subtracted from the pressure on the distal side of the lesion. A reduction in the stenotic gradient after PTCA is a measure of the improvement of vessel architecture affected by the procedure. A stenotic gradient of less than 20 mm Hg after PTCA indicated a successful procedure while a procedure giving a gradient of less than 16 mm Hg is considered to give results equivalent to a coronary artery bypass graft procedure (CABG) .

In 8 of 25 patients, the trans-stenotic gradient was reduced further as a result of prolonged dilatation of the diseased vessel. Improved vessels included six LAD, one RCA and one CIRC. In 7 of the 8 patients, the gradient was reduced to 20 mm Hg or less with the prolonged dilatation—an indication of successful PTCA results.

To achieve coronary flow reserve post-PTCA, which would be equivalent to CABG, the achieved gradient should be 16 mm Hg. Following routine-PTCA, the success of achieving a trans-stenotic gradient 16 mm Hg was only 60%; the success rate was increased to 76% with the prolonged dilatation procedures. The prolonged dilatation also improved the gradient in three patients to 17, 19 and 20 mm Hg from post routine-PTCA levels of 35, 28, and 43 mm Hg, respectively.

Following routine-PTCA, 76% of the patients had reduced gradients lower than the critical gradient associated with a loss of hyperemic reserve (32 mm Hg) . After prolonged dilatation, the success rate was increased to 96% of the patients.

Overall, prolonged dilatation improved the transstenotic gradient in 32% of the patients (mean improvement of 18.6 mm Hg) compared to results following routine-PTCA, suggesting that the artery lumen contour was improved in those patients.

EXAMPLE VIII

Twenty-six patients who presented with a first anterior myocardial infarction were enrolled. Patients were eligible for inclusion if the following criteria were met - age <75 years old, chest pain of >30 min duration unresponsive to sublingual nitroglycerin or nifedipine, or both, no previous myocardial infarction or coronary artery bypass surgery, electrocardiographic (ECG) evidence of ST segment elevation >0.1 mm in any four anterior leads (I, aVL, V, to V₆) and randomization in the emergency room within 4 h of the onset of chest pain. Predetermined exclusion criteria included: persistent hypotension (systolic blood pressure <90mm Hg unresponsive to volume expansion) ; angiographic evidence of spontaneous reperfusion (Thrombolysis in Myocardial Infarction [TIMI] trial grade >l) or significant (>50%) left main stenosis at the time of emergency catheterization, significant valvular disease and a history of hepatic or renal disease.

After randomization, patients were taken for emergency cardiac catheterization. All patients received aspirin (325 mg orally) and Lidocaine (1.5 mg/kg bolus injection followed by 2 to 4 mg/min intravenous infusion) before angiography. Subjects randomized to Fluosol received a test dose of 0.5 ml intravenously and were monitored for 10 min to assess changes in heart rate, blood pressure, respiratory rate and subjective responses.

Following insertion of arterial and venous sheaths, a bolus injection of heparin (10,000 U) was administered intravenously, followed by an infusion of 800 to 1,200 U/h titrated to maintain a partial thromboplastin time two or more times the control value. Left ventriculography was performed in a right anterior oblique projection, followed by visualization of the right and left coronary arteries utilizing numerous standard and orthogonal views.

If the left anterior descending artery was found to be occluded [TIMI] grade 0 or 1 flow) , acute angioplasty was performed utilizing a 0.014 in (0.356 cm) guide wire and an over-the-wire balloon catheter. Typically, three to five inflations lasting 60 to 120 s were performed by using pressure sufficient to achieve full balloon expansion. Once adequate anterograde flow as established (TIMI grade 2 or 3 flow) , the system was withdrawn in the angioplasty group and repeat coronary angiography was performed in identical views before angioplasty.

In patients randomized to Fluosol after angioplasty, the balloon was withdrawn proximal to the site of prior occlusion and an intracoronary infusion of Fluosol commenced utilizing a Medrad injector (Medrad Inc.) at a rate of 40 ml/min for 30 min (total volume 1,200 ml). The Fluosol emulsion was prepared and oxygenated to achieve a partial pressure of oxygen (p0₂) of about 500 mm Hg before infusion, as described herein. Right heart pressures were measured intermittently with a Swan-Ganz catheter. Repeat angiography also was performed in the Fluosol group after removal of the angioplasty system.

All patients then were transferred to the cardiac intensive care unit and were maintained on therapeutic doses of Lidocaine and heparin for 24 to 36 h. Aspirin (325 mg) and diltiazem (90 to 180 mg/day) were given orally during hospitalization. Beta-adrenergic blocking agents were withheld until after hospital discharge. Vascular sheaths were removed on the 2nd hospital day, after which the patients were allowed progressively to ambulate. Patients underwent 24 hr Holter monitoring, thallium-201 single-photon emission computed tomography (SPECT) and repeat cardiac catheterization and ventriculography 7 to 14 days after successful angioplasty. All patients were followed up for a mean of at least 12 months to determine various clinical outcome variables.

Of the twelve patients included in the final analysis, six were allocated to the control group of angioplasty alone and six were allocated to the experimental group of receiving intracoronary Fluosol following angioplasty.

The Fluosol-treated group showed significant improvement of regional ventricular function after reperfusion. The improvement was associated with a significant decrease in infarct size (P<0.05).

All references cited herein are incorporated by reference.

While the invention has been described in detail and with reference to specific examples, it will be apparent to one skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the instant invention.

Claims

WHAT IS CLAIMED IS:

Claim 1. In a human percutaneous transluminal coronary angioplasty procedure following a myocardial infarction, the improvement to reduce reperfusion injury which comprises administering distal to the site of the procedure a reperfusion injury reducing amount of a perfluorocarbon compound emulsion as soon as possible after completion of the procedure.

Claim 2. The process of claim 1, wherein the perfluorocarbon compound emulsion is administered during the reperfusion period.

Claim 3. The process of claim 1, wherein the perfluorocarbon compound emulsion is administered post-operatively.

Claim 4. The process of claim 1, wherein the perfluorocarbon compound emulsion is administered beginning no later than 4 hours after completion of the procedure.

Claim 5. The process of claim 1, wherein the perfluorocarbon compound emulsion is administered beginning no later than 6 hours after completion of the procedure.

Claim 6. The process of claim 1, wherein the perfluorocarbon compound emulsion is administered beginning from about 5 to about 10 minutes after the onset of reperfusion.