Metabolically Controlled Reperfusion in Acute Myocardial Infarction: Should the Polarizing Solution be Given Subselectively?<br />

Acute myocardial infarction (AMI) is characterized by a progressive, irreversible loss of myocardium that results from sustained critical ischemia. Treatment involves recanalizing the occluded culprit coronary artery to restore blood flow, originally by means of systemic fibrinolysis2 and more recently with a catheter device.3 Unfortunately, reperfusion of the ischemic myocardium with blood can, itself, cause arrhythmias and further tissue injury.4 However, substantial laboratory and clinical evidence indicates that ischemic injury may be lessened by the systemic administration of glucose, insulin, and potassium (GIK) before blood reperfusion is begun.5,6 This approach has recently been tested in an ischemic model (the isolated working rat heart)6 and in patients who have had an AMI or have undergone hypothermic ischemic cardiac arrest during cardiac surgery.6,7 Such treatment was inspired by the original clinical work of Sodi-Pallares and his followers.8–10 Beginning in the early 1960s, physicians began to administer an intravenous "polarizing" solution containing GIK during the early phase of an AMI (while the culprit coronary lesion was still totally occluded) in order to reverse the current of injury, restore a normal ion distribution, and improve the heart’s electrical stability. Subsequently, in larger clinical series, administration of GIK in the setting of an AMI was shown to significantly reduce morbidity and mortality.11–13 In the following feasibility study, which was performed in dogs, we addressed various unresolved issues in supported reperfusion by using several innovative approaches. Specifically, we attempted to control the reperfusion process with artificial subselective coronary perfusion, and we tested the hypothesis that the recovery of acutely ischemic myocardium could be improved by introducing a metabolically effective crystalloid solution6 before allowing blood reperfusion. Our final goal was to determine whether the ischemic myocardium could be effectively prepared for blood reperfusion, thereby decreasing blood-related reperfusion injury. Materials and Methods The experimental protocols were approved by the Texas Heart Institute’s Animal Care and Use Committee. The series included 35 mongrel dogs, 6 (17%) of which were female. They were 11–38 months old (mean, 17.4 ± 7.8 months) and weighed 28–44 kg (mean, 35.8 ± 3.5 kg). All the dogs were premedicated with atropine, acepromazine, and oxymorphone and underwent endotracheal tube insertion for mechanical ventilation. Anesthesia was induced with sodium pentothal and was maintained with isoflurane (0.5–2.5%). Pancuronium (Pavulon), 0.1 mg/kg, was used for muscle relaxation. Creation of an ischemic injury. The left carotid artery was surgically isolated and entered with a 7 French (Fr) sheath. A left lateral thoracotomy was performed in the fifth intercostal space, and the pericardium was entered to expose the heart. The arterial blood pressure was monitored through the side port of the carotid sheath. A 7 Fr Judkins or Amplatz guiding catheter was advanced through the sheath to cannulate the left coronary artery. Electrocardiographic monitoring was done with peripheral and precordial leads. Preliminary left coronary angiography was performed. Under fluoroscopic control, a 0.014´´ guidewire was then introduced into the left anterior descending artery (LAD), and a coronary perfusion catheter (Corflo®; Angiodynamics, Queensbury, New York) was advanced to the mid portion of the LAD. A left atrial line was inserted through the left atrial appendage to allow or left ventricular angiography. A catheter was surgically introduced into the coronary sinus and was advanced into the anterior cardiac vein to monitor biochemical changes in blood draining from the affected area of myocardium. A removable ligature was applied to the LAD, between the first and second diagonal branches, over the perfusion catheter, and was kept in place for 90 minutes (Figure 1). To prevent or treat arrhythmias, boluses of intravenous lidocaine (50 mg) and/or brethylium (150 mg) and/or propranolol (1 mg) were given as required. During the initial open-chest intervention, internal cardiac massage was performed (if needed) for a maximum of 30 minutes. All visible collateral vessels were ligated between the LAD and the first diagonal, obtuse marginal, or posterior descending branch. Typically, three collateral branches were ligated to ensure total ischemia. Reperfusion protocols. After the LAD territory had been ischemic for 90 minutes, each dog was randomly assigned to 1 of 3 groups, based on the reperfusion protocol instituted (Figure 2). In Group I (11 dogs), the control group, the coronary ligature and perfusion catheter were removed, allowing immediate blood reperfusion. In Group II (11 dogs), a modified GIK solution (Table 1) was subselectively administered to reperfuse the ischemic myocardium for 30 minutes. Because initial experiments using a 10% dextrose solution (in 8 dogs) yielded unfavorable results, lower dextrose concentrations (Table 1) were used for the remaining experiments. In Group III (7 dogs), both propionyl-L-carnitine (PLC) (Provided by Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, Maryland) and the GIK solution were subselectively infused for 30 minutes. In the active treatment groups (II and III), the perfusate was administered by means of a special coronary pump (Corflo, Angiodynamics) at 30–50 mL/minute. Oxygenation of the solution was achieved with a bubble oxygenator (Sorin Biomedica, Arvada, Colorado) and a roller pump (Terumo Cardiovascular System, Ann Arbor, Michigan), which yielded a PO2 of about 700 mmHg in the crystalloid solutions. Temperature homeostasis of the perfusate was achieved with a Terumo cooler/heater set at 37 ºC. After the initial artificial reperfusion period, all the animals were allowed to have spontaneous blood reperfusion and to recover in the operating room for 90–180 minutes. At the end of this period, all the catheters were removed, and the chest was closed. The left carotid artery was either repaired or ligated. The dogs were then extubated, and pain medication was given routinely, by means of a butorphanol tartrate patch. Antibiotic prophylaxis was routinely carried out with a 1-g intravenous infusion of ceftazidime. On days 3–5, with the aid of general anesthesia and endotracheal intubation, the thoracotomy wound was reopened, left ventriculography was carried out, and each dog was sacrificed with an intravenous bolus of pentobarbital sodium and phenytoin sodium (Beuthanasia), 0.22 mL/kg. Histologic and statistical analyses. The myocardial infarct size and area at risk were measured with the triphenyl tetrazolium chloride (TTC) method.14 Serial sections of the myocardium were obtained for histologic evaluation using hematoxylin-eosin and trichrome dyes. The endpoints were: 1) mortality related to ventricular arrhythmias versus cardiogenic shock and/or heart failure; 2) the ratio of the myocardial infarct size/area at risk 3 to 5 days postoperatively (as assessed with the TTC method); and 3) specific histologic features, including intramural hemorrhage and (micro)vascular or myocyte changes. For statistical analysis, "arrhythmias" were considered only if they required treatment (intravenous medication, cardiac massage, or electric shock). Quantitative values were expressed as the mean ± standard deviation. Student’s unpaired t-test was used to compare the two groups. Significance was set at p Effects of LAD artery ligation. The angiographic left ventricular ejection fraction (EF) (available for 11 dogs) was 47.6 ± 13.5% before LAD ligation and 34.9 ± 10.8% during LAD ligation, when gross inspection and ventriculography consistently showed large anteroapical areas of dyskinesia (Table 2). At follow-up angiography on postoperative days 3–5, the EF for the whole series had decreased to 31.0 ± 11.8% in the 11 dogs for which serial data were available (p = 0.2). Interestingly, as shown in Table 2, the EF at follow-up had decreased further (since ligation) in Group III (28.8 ± 10.3% to 23.7 ± 5.1%; p = 0.05) but not in Group II (36.6 ± 10.5% to 39.8 ± 11.8%; p = 0.06). During LAD ligation, the systolic blood pressure initially decreased by 10–25 mmHg, but most (28/29) of the dogs showed hemodynamic tolerance of ligation. Lethal ventricular fibrillation developed in only one dog during the initial phase of total ischemia. In all cases, the precordial electrocardiographic tracings showed an acute injury pattern during LAD ligation. Effects of the different reperfusion protocols. The initial adverse ST-segment changes were immediately improved or eliminated by GIK infusion (with or without PLC) but not by blood reperfusion alone (Group I). During the initial 30 minutes of reperfusion with GIK (Group II), the systolic wall motion of the myocardium (although exsanguinated) appeared to recover only partially, as evaluated by gross inspection and left ventricular angiography. Immediately after blood reperfusion, a high incidence of severe ventricular arrhythmias (typically ventricular fibrillation) was observed in Groups I and II; this complication was less frequent in Group III (Table 3). In the latter group, local ventricular function underwent severe deterioration shortly after the initiation of blood reperfusion. With the advent of total akinesia, wall stiffness increased, and diffuse subendocardial ecchymotic spots began to appear in the affected area. In the solutions used for the reperfusion cocktail, effective concentrations of dextrose varied (Table 1). The resulting osmolality of each solution’s formula varied from 1.0–1.6 (the baseline osmolality of Ringer’s solution being 1.0, or physiologic). The incidence of ventricular fibrillation (and mortality) correlated with increased osmolality (Figure 3). The individual potassium and calcium serum levels were all within the normal range and did not correlate with, or explain, the onset of ventricular fibrillation. The mean potassium levels in the coronary sinus were lower in group I (3.3 ± 0.7 mEq) than in Groups II (4.1 ± 0.8 mEq) and III (4.6 ± 0.7 mEq), which were within normal limits. The 10% dextrose GIK formula resulted in a high (7/8 or 87.5%) perioperative mortality related to arrhythmias. The mortality was lower in the dogs with 5% dextrose (1/5 or 20%; p

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