Anoxic Arrest Research Articles

Late clinical and arteriographic results in 500 coronary artery reoperations

The incidence of coronary artery reoperations averaged 2.7% from 1967 through 1979. In a mean interval of 51 months between operations, three-vessel disease increased from 24% to 63%, and 31% of these 500 consecutive patients lost previously normal left ventricular function. Three angiographic indication groups were identified: (1) progressive coronary atherosclerosis, 247 (51%); (2) graft failure, 147 (29%); and (3) a combination of progressive coronary atherosclerosis and graft failure, 96 (19%). Angina recurred earlier in patient with graft failure, mean 17 months compared with a mean of 37 months for the other groups. Twenty (4%) operative deaths occurred. The series is divided into 387 patients operated upon under normothermic anoxic arrest and 113 with systemic hypothermia and cold cardioplegia. In the cardioplegia group, perioperative myocardial infarction was 2.7% in comparison with 7.8% for patients with anoxic arrest (p = 0.055). The number of grafts per patient increased from 1.0 to 1.9 and blood usage decreased from 11 units to 2.7 units. After a mean follow-up of 42 months, angina was relieved or improved in 86%. Recatheterization of 104 patients after a mean interval of 19 months showed a 79% vein graft patency rate and a 97% mammary artery graft patency rate. Grafting performed for graft failure (47) yielded an 85% patency rate. Actuarial 5 year survival was 87.4% for those with progressive atherosclerosis, 89.4% for patients with graft failure, and 91.5% for the combined indication group. Clinical improvement, graft patency, and long-term survival are nearly equal among the indication groups. Palliation derived from these reoperations approaches that achieved after primary revascularization.

Is Reperfusion Injury from Multiple Aortic Cross-Clamping a Current Myth of Cardiac Surgery?

Four hundred eighty adult patients undergoing cardiac operations had systemic and topical hypothermic anoxic arrest supplemented with potassium chloride pharmacological cardioplegia in a prospective randomized study. Group 1 (217 patients) had continuous aortic cross-clamping and one single anoxic arrest period during the cardiac portion of the operation which resulted in a transmural myocardial infarction rate of 8.3%, myocardial “injury” incidence of 12.4%, 4.6% cardiac-related deaths, 11.5% and 24.8% severe and malignant ventricular arrhythmias, 21.7% rate of severe vasopressor usage, a mean group serum glutamic oxaloacetic transaminase (SGOT) of 140 ± 39 IU, and a mean group lactic dehydrogenase (LDH) of 636 ± 78.2 IU. Group 2 (263 patients) had intermittent aortic cross-clamping with multiple reperfusion intervals, which resulted in a significantly lower incidence of transmural myocardial infarction at 1.9% ( p < 0.01), rate of myocardial injury at 5.66% ( p < 0.02), number of cardiac deaths at 0.76% ( p < 0.02), 8.7% and 16.0% severe and malignant ventricular arrhythmias ( p < 0.01), severe vasopressor utilization rate of 14.3% ( p < 0.05), mean group SGOT at 72.0 ± 3.1 IU ( p < 0.01), and mean group LDH at 471.0 ± 12.3 IU ( p < 0.05) than Group 1. These results do not support the contention that intermittent aortic cross-clamping in conjunction with hypothermia and pharmacological cardioplegia leads to increased clinical cardiac damage compared with continuous aortic cross-clamping. The converse is implied, in that the anoxic heart may benefit from the physiological effects of briefly reperfused oxygenated blood.

Ultrastructural and cytochemical correlates of myocardial protection by cardiac hypothermia in man

We report observations on ultrastructural and cytochemical changes in the myocardium after hypothermic protection in 21 patients who underwent cardiac operation. Two general categories of hypothermic protection were studied. (1) topical cooling during anoxic arrest and moderate general hypothermia (10 patients with aortic valve replacement, Group 1) and (2) intermittent perfusion during moderate general hypothermia combined with topical cooling (11 patients with multiple valve replacement, Group II). Transmural left ventricular biopsies were taken at the start of the cardiopulmonary bypass and shortly after the end of aortic cross-clamping. In Group I (cross-clamp time, 51 +/- 12 minutes) only minor pathologic changes of the myocardial fine structure were found, with no differences among the left ventricular layers. In most mitochondria, structure remained intact but the mitochondrial granules disappeared. Cytochrome-c-oxidase activity was unchanged. In Group II (total cross-clamp time, 83 +/- 16 minutes) the subendocardium was well preserved. Slight subcellular damage comparable with that of resulting from topical cooling was seen in all hearts even after a total cross-clamp period of 106 minutes. Cytochrome-c-oxidase activity was unchanged. In the subepicardium, however, a positive correlation was found between the severity of ultrastructural damage and total cross-clamp time (p less than 0.05). Matrix clearing, damage to the cristae and the mitochondrial membranes, and nuclear abnormalities occurred when the aorta was cross-clamped for morethan 60 minutes. Cytochrome-c-oxidase activities decreased in these samples. It is concluded that: (1) no significant subcellular injury was found in hearts cooled topically during 1 hour of anoxic arrest; and (2) in hearts protected by intermittent perfusion during moderate general hypothermia and additional external cooling, the subendocardium was well preserved for anoxic periods of up to 106 minutes. However, after 60 minutes of aortic cross-clamping subcellular damage increased progressively in the subepicardium.

Effects of extracorporeal circulation on cardiac performance and coronary blood flow (total and regional). A study of differences arising from pre-existent left ventricular load and anoxic arrest.

It was researched how the ECC affects on cardiac performance and the total and regional coronary blood flow, using two groups of dogs with a hypertrophied heart and a non-hypertrophied heart, each group of which was further divided into two subgroups depending on whether the intermittent 40 mins. anoxic arrest was applied or not. Cardiac performance before and 60 mins. after cessation of ECC were compared each other. Coronary hemodynamics was studied before, during (immediately before and after anoxic arrest), and 60 mins. after cessation of ECC, using 15 +/- 5 diameter radioactive microspheres. 1) In the group of a non-hypertrophied heart, no obvious changes of cardiac performance were seen before and after ECC. The total coronary blood flow increased after ECC than before. Though the regional coronary blood flow pattern showed no differences in this group except only immediately after anoxic arrest, when the regional blood flow into the right ventricle, inner and middle layers of the left ventricle increased. 2) In the group of a hypertrophied heart, cardiac performance decreased after ECC, and further significant decrease was observed in the subgroup of anoxic arrest. No significant changes of the total coronary blood flow were observed before and after ECC in this group, even when compared with that in the group of a non-hypertrophied group. However, the increase of blood flow to the right ventricle, inner and middle layers of the left ventricle immediately after anoxic arrest was not observed, that was seen in the group of a nonhypertrophied heart. 3) It follows that the decrease of cardiac performance after ECC in the group of a hypertrophied heart is not due to the changes of the total and regional coronary blood flow. It is considered that the difference of the regional coronary blood flow pattern changes immediately after anoxic arrest between the non-hypertrophied heart group and hypertrophied group may cause the different changes of cardiac performance before and after ECC between the two groups. This consideration should be more justified by evaluating not only coronary hemodynamics but also the relationship between cardiac metabolic needs and the regional coronary blood flow.

Effect of noncoronary blood flow upon myocardial mitochondrial function during hypothermic anoxic arrest.

Mongrel dogs (23) were subjected to the experimental study characterizing the effect of noncoronary blood flow upon myocardial mitochondrial respiration. Anoxic arrest for 60 minutes was obtained by cross-clamping of the aorta under hypothermic cardiopulmonary bypass, and heart was reperfused for 10 minutes, then heart was excised to obtain the endocardium, epicardium of the left ventricle and ventricular septum for study of mitochondrial function and myocardial blood flow. Myocardial blood flow was measured with carbonized plastic tracer 46Sc during cross-clamping of the aorta. Noncoronary blood flow showed equal distribution in the left ventricle and septum with flow of 0.16 +/- 0.23 ml/ min/100g (endocardium). Mitochondrial respiratory function following 60 minutes of hypothermic anoxic arrest at 20 degrees C recovered to normal level, and also no correlation was demonstrated between noncoronary blood flow during cross-clamping of the aorta and mitochondrial respiratory function. It was concluded that noncoronary blood flow was negligible with respect to the oxygen demand at 20 degrees C of myocardial temperature, and that noncoronary blood flow during cross-clamping of the aorta was not correlated to mitochondrial protection from ischemia.

Myocardial respiration and edema following hypothermic cardioplegia and anoxic arrest

The effects of 1 and 2 hours of hypothermic anoxic arrest and cardioplegia induced by Mg-lidocaine, K-Mg, or K on left ventricular mitochondrial respiratory function, blood flow, and edema were studied in 41 mongrel dogs. Mitochondrial respiration was assessed by the indices of oxidative phosphorylation. Myocardial temperature recorded in ventricular septum was kept at 20 degrees C during ischemic arrest and 10 minutes of reperfusion. Cardioplegic solutions did not influence noncoronary blood flow during cross-clamping of the aorta. Mitochondrial respiratory function remained at control levels after 1 hour of ischemia induced by hypothermic anoxic arrest or by Mg-lidocaine or K-Mg hypothermic cardioplegia. Mitochondrial state 3 respiration after 2 hours of anoxic arrest was significantly higher in Mg-lidocaine cardioplegia than in anoxic arrest (p less than 0.05), but myocardial edema was equivalent in both groups. Mg in the cardioplegic solution suppressed mitochondrial nonphosphorylating oxygen consumption. These data suggest that mitochondrial function after 1 hour of ischemic arrest at 20 degrees C and 10 minutes of reperfusion is not significantly depressed, but at 2 hours of ischemic arrest, mitochondrial respiration is significantly impaired. However, hypothermic Mg-lidocaine cardioplegia appears to be more effective in sustaining myocardial respiration than does simple hypothermic anoxic arrest when the anoxic period is extended to 2 hours.

The use of steroids as a potentiator of hypothermic myocardial preservation in man

Profound hypothermic preservation (15–18°C) of the arrested myocardium offers the best protection against ischemic changes and potassium cardioplegia potentiates this preservation by allowing a more dynamic postbypass recovery, but at the cost of increased intra- and extracellular edema and mitochondrial injury. This study assesses the protective value of a steroid in the perfusion solution, methylprednisolone sodium succinate (1 g/liter), in the presence of profound hypothermic (myocardial T < 20°C) potassium (K = 26 meq/liter) cardioplegia. In a randomized prospective blinded study two groups (control A and steroid B) of 10 patients undergoing a minimum of three coronary bypass grafts were compared by clinical, cardiodynamic, electron microscopic biopsy, and mixed venous lactate and creatine phosphokinase (CK-MB) isoenzyme studies. The mean anoxic arrest time and number of grafts per patient were comparable. Although the CK-MB isoenzyme levels were lower in the postoperative period in the Solu-Medrol group, this was not statistically significant. The clinical course of the two groups was similar, however the control group of patients required a far greater degree and duration of inotropic support to attain comparable recovery trajectories to the Solumedrol group of patients. Critical ultrastructural differences in the steroid-treated group were better mitochondrial preservation, increased perimitochondrial glycogen stores, and a reduction in intracellular edema. These results suggest that steroids may enhance stabilization of cellular metabolic processes under conditions of hypothermic potassium cardioplegia.

Subendocardial protection during cardiopulmonary bypass. Its use with methylprednisolone and glucose-insulin-potassium.

Fifteen adult dogs were equally divided into three groups: group 1 (control) received no medication before or after cardiopulmonary bypass (CPB), group 2 was administered glucose-insulin-potassium (GIK) according to Maroko's protocol before, during, and after CPB, whereas group 3 was treated with methylprednisolone (30 mg/kg) 30 minutes prior to and near the end of CPB. Moderately severe subendocardial hemorrhage was present in 80% of group 1, 50% of group 2, and only 20% of group 3 ventricles. Endocardial viability ratios after CPB were greater than 0.75 in 20% of group 1, 80% of group 2, and 100% of group 3 animals. Both GIK and steroids improved subendocardial perfusion after anoxic arrest and CPB compared with controls. However, steroid-treated dogs exhibited less endocardial hemorrhage, improved contractility, and more rapid return to baseline conditions than either GIK or control animals. These data suggests that steroids could be considered whenever normothermic anoxic cardiac arrest is used for cardiac operations.

Quantitative evaluation of myocardial ultrastructure following hypothermic anoxic arrest

Thirty-six anesthetized mongrel dogs were subjected to systemic hypothermia and anoxic cardiac arrest while on cardiopulmonary bypass. Myocardial fine structure in the left ventricle was evaluated by quantitative analysis in the subepicardial, mid-myocardial, and subendocardial layers. The specimens were obtained by a transmural myocardial biopsy method. Graded hypothermia was employed at 36 degrees, 30 degrees, 28 degrees, 25 degrees, and 22 degrees C. The aorta was cross-clamped for 30 minutes at 36 degrees, 30 degrees, 28 degrees, and 25 degrees C. or for 45 minutes at 25 degrees and 22 degrees C. Observations indicated that pathological changes of the myocardial fine structure were significant after anoxic arrest in the normothermic group. Lesions were most extensive in the subendocardial layer after normothermic anoxic arrest, whereas hypothermia below 30 degrees C. preserved the myocardium throughout all layers without difference in pathological changes in the fine structure among the layers. Mitochondria and glycogen granules in the mid-myocardial layer and the subendocardial layer were best preserved with hypothermia at 25 degrees and 22 degrees C. after 30 minutes or 45 minutes of anoxic arrest, and dogs in these groups had a survival rate of 100 percent. Quantitative analysis of ultrastructural changes induced in these experiments suggest that a safe duration of anoxic arrest at 22 degrees to 25 degrees C. is between 30 and 45 minutes.

The effect of blood oxygen content and the no-reflow phenomenon on the subendocardial ultrastructural reversibility following anoxic arrest using hemodilution variables in the experimental model.

Hemodilution is an accepted modality for the conduct of cardiopulmonary bypass. The degree of hemodilution clinically employed has been in the range of 20 per cent of the initial hematocrit levels. This study was designed to evaluate the effects of hemoglobin levels and oxygen content on the reversibility of the damaged or altered ultrastructure of the endocardial layer of the ventricle and the possible role of the no-reflow phenomenon. Two series of mongrel dogs were subjected to cardiopulmonary bypass at normothermic levels and a standard period of ischemic arrest. One series was with hemoglobin levels between 5 and 10 grams (mean 7.25 grams) designated as moderate hemodilution (MH). The second series was of hemodilution with less than 5 grams of hemoglobin (mean 4.8 grams) designated as severe hemodilution (SH). The ultrastructural alteration gradient (UAG) between the epicardium and endocardium was studied with its relationship to reversibility of myocardial function and animal survival. The study demonstrated a definitive relationship between oxygen content and the reversibility of myocardial damage under normothermic conditions and anoxic arrest. The poor survival results in the SH group; two of 12 are attributed to the low oxygen availability possibly triggering the no-reflow phenomenon which prevents reversibility of the myocardial ultrastructural damage and ultimately the functional integrity of the ventricle.

Potassium-induced cardioplegia

Potassium-induced cardioplegia during anoxic arrest was utilized in a study of 190 consecutive patients undergoing revascularization (average 2.8 grafts per patient) from August, 1975, through August, 1976. Surgical technique, moderate systemic hypothermia with intermittent anoxic arrest, and the surgeon were the same for all patients. One hundred thirty-five patients (KC1-treated) received a bolus (150 ml.) of potassium solution injected into the proximal aortic root whenever the aortic cross-clamp was applied; 55 others served as control subjects. The mortality rate was 2.2% (three of 135) in the KCl-treated group and one of 55 in the control group. New Q waves appeared in 5.9% (eight of 135) of the KCl-treated patients and 11% (6 of 55) of control subjects (p = N.S.). Catecholamine drips were required after bypass in 4.4% (six of 135) of patients given potassium and 18% (10 of 55) of control patients (p less than 0.05). Profound myocardial relaxation was of added technical value with potassium. It is our impression that hearts treated with potassium exhibited more prompt cardioversion, separated from cardiopulmonary bypass with less need for inotropic support, and exhibited less myocardial injury during the revascularization procedure.

The protective effect of magnesium-aspartate-procaine cardioplegia on the hypertrophied left ventricle of the mini-pig (author's transl)

After induction of left ventricular hypertrophy by supravalvar constriction of the ascending aorta in mini pigs (ATP and lactate) were measured under different cardioplegic conditions. In normothermia and plain anoxic arrest ATP decrease and lactate increase were significantly slower in hypertrophied myocardium compared to normal myocardium. Injection cardioplegia using magnesium-aspartate-procaine at 37 degrees C did not influence the ATP decrease and lactate increase in the hypertrophied ventricle, whereas in the normal heart it showed some protection according to these parameters. Optimal ATP preservation and the lowest lactate increase rate were achieved in left ventricular hypertrophy by combined application of magnesium-aspartate-procaine and hypothermia of 25 degrees C. We conclude that normothermic injection cardioplegia has no protective effect on the hypertrophied left ventricle, whereas additional hypothermia can improve magnesium-aspartate-procaine cardioplegia significantly.

A Simple Method of Cold Coronary Perfusion

Hypothermic coronary perfusion lengthens the safe duration of anoxic arrest. Intermittent selective hypothermic coronary perfusion provides extended myocardial protection. We describe a method of achieving profound myocardial hypothermia by selective deep hypothermic coronary perfusion using a cooling coil without a separate pump head.

Myocardial Alterations Associated with Aortocoronary Saphenous Vein Bypass

Clinical observations and gross and microscopic morphology of the hearts of 50 patients who dies at various intervals following aortocoronary saphenous vein bypass procedures are presented. Time of total cardiopulmonary bypass varied inversely with survival time among these patients. Myocardial necrosis with contraction bands and/or hemorrhagic myocardial necrosis was observed in the hearts of 44 of the 50 patients. Pathogenesis of the acute myocardial necrosis with contraction bands was multifactorial: anoxic arrest, cardiotonic drugs, electrical defibrillation, electrolyte imbalance, microthrombi, and hypoperfusion are incriminated. Subendocardial hemorrhagic necrosis was present in 17 of 40 patients whose postoperative survivals were four days or less. Its frequency increased with duration of survival. Hypoperfusion of the myocardium is suggested as the major etiologic factor of the subendocardial hemorrhagic necrosis. Myocardial lesions observed among these 50 patients did not differ from those in patients who had open-heart surgery for other reasons.

Left ventriculotomy for closure of muscular ventricular septal defects. Treatment of choice.

Closure of muscular ventricular septal defects (VSDs) through the right atriotomy or right ventriculotomy may be difficult. These VSDs are often located behind the hypertrophied trabeculae carnae or papillary muscle. Residual or recurrent VSD may result from the difficult approach. Between March 1971 and December 1975, we have used the left ventriculotomy near the apex for closure of muscular VSDs in ten children. The patients' ages ranged from five months to eight years and three months. The diagnosis was established by cardiac catheterisation and left ventricular angiocardiogram in all patients. Six patients had multiple VSDs; in four patients VSD in the muscular septum was present (three apical, one midseptal). Operations were performed on cardiopulmonary bypass with moderate hypothermia and intermittent anoxic arrest. VSDs in the membranous septum were closed through the right atrium. Muscular VSDs were approached through a small vertical incision in the left ventricle near the apex. The postoperative course was uneventful in eight patients. Two patients, aged 16 months and eight years, died; histology showed grade IV pulmonary vascular disease in both. All survivors are well four months to five years after the operation, without clinical evidence of residual or recurrent VSD.

Advantages of Potassium Cardioplegia and Perfusion Hypothermia in Left Ventricular Hypertrophy

An attempt was made to determine the effect of hypothermic potassium cardioplegia (35 mEq of potassium chloride) on the hypertrophic ventricle. Puppies with induced left ventricular hypertrophy were divided into four groups and studied after one hour on global ischemia. Myocardial adenosine triphosphate (ATP) was best preserved in the hypothermically perfused groups and correlated well with measurements of coronary sinus creatine Phosphokinase (CPK). In Groups 1 and 2 (anoxic arrest at 37°C and KCl perfusion at 37°C), CPK at 30 minutes of reperfusion was 1,031 and 198 IU, respectively, compared to 35 IU in Group 3 (KCl perfusion at 4°C) and 44 IU in Group 4 (Ringer's lactate at 4°C). Myocardial injury was milder in Groups 3 and 4 regardless of whether potassium chloride was added. It is apparent that hypothermic perfusion of a hypertrophic ventricle was the major factor in myocardial preservation, as determined by myocardial ATP and coronary sinus CPK.

The Haematoxylin-basic Fuchsin-picric acid staining reaction as a test of myocardial viability in resuscitated and preserved hearts.

In the field of the transplantation of organs, there is a great need for an in vitro test of viability which would confirm that the organ was capable of performing its normal in vivo functions. Such a test should ideally be simple, rapid and reproducible. Preliminary studies using the Haematoxylin-Basic Fuchsin-picric acid (HBFP) staining reaction to assess myocardial ischaemia in resuscitated and preserved hearts would suggest that this test meets many of the requirements of a viablility assay. The test has been employed in hearts which have been in a state of anoxic arrest for 30 min and then resuscitated and preserved as an autoperfusing heart-lung preparation. The 'positive' response after 30 min anoxic arrest reverts to a 'negative' response after 2 h myocardial perfusion. In hearts which have been preserved as an autoperfusing heart-lung preparation with no interim period of anoxic arrest the HBFP stain response remains 'negative' throughout, confirming satisfactory myocardial perfusion.

Selective Intracavitary and Coronary Hypothermic Cardioplegia for Myocardial Preservation

Intraoperative myocardial protection was evaluated in two groups of patients undergoing coronary surgery in whom different techniques for cardiac arrest were utilized. In group A, profound selective myocardial hypothermic (15 to 18 C) arrest was achieved by perfusing a coolant (7 to 10 C) into the left ventricular cavity and the coronary circulation. The average anoxic arrest time was 82.5 +/- 27 minutes. In group B, ventricular fibrillation and moderate hypothermia were used. Group A patients showed rapid physiologic recovery, low average myocardial creatinine phosphokinase (MB-CK) isoenzyme levels (7.8 IU) , and a well-preserved myocardial ultrastructure. In group B, three patients showed abnormal physiologic recovery; six patients needed postoperative inotropic support; and in seven patients, electron-microscopy revealed irreversible focal changes. The average MB-CK isoenzyme level was 85.6 IU. Analysis of our data demonstrates that when myocardial protection during coronary bypass grafting is achieved by selective profound intracavitary and coronary cooling, there is physiological, ultrastructural, and biochemical evidence of less intraoperative myocardial damage than when ventricular fibrillation is applied.

A New Approach to Left Heart Decompression

A simple, safe, indirect technique for decompression of the left heart is described. Pulmonary artery venting produces immediate and total decompression of the left heart through spontaneous retrograde pulmonary flow across the open mitral valve in the hypothermic (29°C) electrically fibrillated heart. This allows free retrograde flow of left heart blood across the pulmonary valve into the right ventricle, where it is taken up by the usual caval cannulas. In 25 of 66 consecutive patients undergoing elective ventricular fibrillation and anoxic arrest, left heart venting was necessary as indicated by rising left heart pressures. Total cardiac decompression was immediately and completely achieved by this simple indirect technique. Direct left heart venting, with its associated risks and disadvantages, was never necessary, and we now consider it obsolete.

Internal mammary artery bypass graft in reoperative myocardial revascularization

Thirty-two consecutive patients who earlier received indirect or direct myocardial revascularization underwent reoperation with one or more internal mammary artery grafts either alone or in combination with saphenous vein grafts. The main indication for reoperation was graft closure or progression of coronary atherosclerosis in nongrafted vessels, or both. Graft construction was performed under normothermic perfusion and anoxic arrest with interrupted suture technique. No intraoperative infarctions or hospital deaths occurred. All patients are alive after an average follow-up period of 20 months, and two thirds are asymptomatic. Arteriography after reoperation in nine patients revealed patency of eight of nine internal mammary artery and five of five secondary vein grafts. When angiographic and symptomatic indications for reoperation exist, the internal mammary artery bypass graft has become a valuable alternative, particularly for patients with small coronary vessels or previous vein graft failure.