Intermittent aortic cross-clamping versus St. Thomas’ Hospital cardioplegia in extensive aorta-coronary bypass grafting

J

THORAC CARDIOVASC SURG

88:164-173,1984

Original Communications

Intermittent aortic cross-clamping versus 81. Thomas' Hospital cardioplegia in extensive aorta-coronary bypass grafting A randomized clinical study Myocardial preservation was assessed in 72 patients undergoing exteesire myocardial revascularization. The patients were allocated at random to three surgical techniques: Group 1, intermittent aortic cross-clampingat 32° C; Group 2, intermittent aortic cross-clamping at 25° C; and Group 3, St. Thomas' Hospital cardioplegia. As intraoperative markers of ischemic damage, adenosine triphosphate, creatine phosphate, and glycogen contents were determined in trammuralleft ventricular biopsy specimens taken at the beginning and at the end of cardiopulmonary bypass.Ultrastructure was studied in a similar pair of biopsy specimens. Release of myocardium-specific creatine kinase isoenzyme was determined intraoperatively and postoperatively. Functional recovery was assessed before and after weaningfrom cardiopulmonary bypass. The incidence of lowcardiac output, myocardial infarction, and rhythm disturbanceswas compared betweengroups. FmaIIy, actuarial survival and event-free curveswere studied after 18 months' foUow-up. The results show a better preservation of high-energy phosphates,glycogen, and ultrastructure in the cardioplegia group as compared to the two cross-clamp groups. However, severe myocardial damage was neverobserved. Release of MB creatine kinase isoenzyme was the same in all three groups. Functional recovery of the hearts immediately after cessation of cardiopulmonary bypass was better in the cardioplegia group, but the incidence of rhythm disturbances (atrioventricular conduction problems) was higher in the cardioplegiagroup than in the other two groups (p < 0.05).Clinicaloutcome in terms of incidenceof perioperative infarction, survival, and event-free foUow-up was not different betweengroups. It is concluded that both techniques (aortic cross-clamping at 32° C or 25° C and St. Thomas' Hospital cardioplegia) offer good myocardial protection in extemive aorta-coronary bypass operations. St. Thomas' cardioplegia, however, in contrast to intermittent aortic cross-clamping, prevents the onset of ischemia-induced deterioration of cardiac metabolism, i.e., destruction of the adenine nucleotide pooL

Willem Flameng, M.D., Ger J. Van der Vusse, Ph.D., Roland De Meyere, M.D., Marcel Borgers, Ph.D., Paul Sergeant, M.D., Eugene Vander Meersch, M.D., Jef Geboers, and Raf Suy, M.D., Leuven and Beerse, Belgium. and Maastricht, The Netherlands

From the Department of Cardiovascular Surgery, Department of Anaesthesiology, and Division of Epidemiology, University Clinic St. Rafael, Leuven, Belgium, Janssen Research Laboratories, Beerse, Belgium, and Department of Physiology, University of Maastricht, The Netherlands. Supported by the Dutch Heart Foundation.

164

Received for publication July 25, 1983. Accepted for publication Nov. 7, 1983. Address for reprints: W. Flameng, M.D., Department of Cardiovascular Surgery, University Clinic St., Rafael, Capucijnenvoer 35, B-30oo Leuven, Belgium.

Volume 88 Number 2 August, 1984

As pointed out recently, there is no single best method for myocardial protection at present. There seem to be as many strategies and magic cardioplegic solutions as there are investigators.' However, in coronary bypass operations, two main techniques of myocardial protection can be recognized: cardioplegia (blood or crystalloid) and intermittent aortic cross-clamping. Although both techniques have their "pros and cons" from the surgical point of view," their protective effects have not been compared in the clinicalsetting in a well-designedrandomized study. It is no longer acceptable to evaluate myocardial protection simply by monitoring operative mortality or the need for inotropic drugs or intra-aortic balloon support when the patient is being weaned from cardiopulmonary bypass (CPB). Even postoperative electrocardiographic changes, myocardium-specific serum enzyme elevations, or radionuclide ejection fraction studies alone may not be sufficient.I More sophisticated methods are now available, and subtle damage that occurs during cardiac operations can be detected by the assessment of highenergy phosphates and glycogen or by the study of ultrastructural damage to the myocardial cells.' We believe that the combination of criteria from simple mortality figures to electron microscopy of the myocardium is needed to determine the superiority of a given cardioprotectivetechnique. Furthermore, the study must be a randomized prospective clinical trial. We designed the present study with all of these considerations in mind. We compared the St. Thomas' Hospital cardioplegic solution with two types of intermittent aortic cross-clamping: at normothermia (32° to 35° C) and at hypothermia (25° C). The study was performed in 72 randomized patients undergoing aortacoronary bypass grafting. The following markers of ischemia and ischemic injury were studied: depletion of high-energy phosphates and glycogen, changes in ultrastructure of the myocardium during the operation, release of the MB isoenzyme of creatine kinase (CK-MB) immediately after the operation, recovery of hemodynamics after weaning from CPB, the need for inotropic support, the incidence of myocardial infarction and rhythm disturbances, and fmally the clinical outcome in terms of mortality and symptomatic improvement after 18 months' follow-up.

Methods Surgical procedure. Seventy-two adult patients were studied during aorta-coronary bypass grafting. These *Johnson

WD: Personal communication.

Intermittent cross-elamping versus cardioplegia 16 5

patients were randomized into three groups: Group I-intermittent aortic cross-clamping at 32° to 35° C (normothermia); Group 2-intermittent aortic crossclamping at 25° C (hypothermia); and Group 3continuous aortic cross-clamping at 25° C plus infusion of St. Thomas' Hospital cardioplegic solution (cardioplegia group). Criteria for inclusion in the study were as follows: three-vessel disease necessitating at least four distal anastomoses, no signs of acute myocardial infarction, and no associated cardiac disease including left ventricular aneurysm. All patients had recurrent angina managed with nitrates and beta adrenergic blocking agents. Patients with evidence of congestive heart failure or with ejection fractions of 30% or less were receiving digitalis preparations. Beta blocking agents were maintained until the evening before the operation. Digitalis was discontinued the day before the operation. After anesthesia, a flow-directed balloon-tipped 7 Fr. Edwards thermodilution catheter was passed from the right internal jugular vein to the pulmonary artery. An isotonic solution (Normosol-R pH 7.4) was administered in volumens adequate to maintain a pulmonary capillary wedge pressure at control values (8 mm Hg for patients with a normal ventricular function). After heparinization (300 IV . kg-I) and cannulation of the aorta, a 7 Fr. Philips or Millar tip manometer was placed into the left ventricle via the right pulmonary vein. CPB was conducted with a Harvey H -1500, a Bentley Spiraflo BOS-IO or a Shiley looA disposable bubble oxygenator and Sarns roller pumps. Immediately after the onset of CPB, a pair of left ventricular transmural biopsy specimens were taken (Tru-Cut Travenol biopsy needle) from the anterior free wall approximately 5 em above the apex. Thereafter, patients in Groups 2 and 3 were cooled to 25° C; those in Group 1 cooled spontaneously to 32° to 35° C. Next the heart was vented via a cannula inserted into the left ventricle via the left atrial appendage. Intermittent aortic crossclamping was used in Groups 1 and 2 to perform the distal anastomosis. Mean aortic cross-damp time was 11.1 minutes per anastomosis, and the mean reperfusion period between two successive periods of cross-clamping was 10 minutes. In the cardioplegia group, after cross-clamping of the aorta, St. Thomas' Hospital cardioplegic solution' was infused via a roller pump into the aortic root with a perfusion pressure (aortic root pressure) of 50 mm Hg. Septal temperature was monitored. Initially, 700 ml of the solution was infused. Septal temperature varied between 8° and 15° C. Every 20 minutes the solution

The Journal of Thoracic and Cardiovascular Surgery

1 6 6 Flameng et al.

Table I Preop. M/

No.

Age (yr)

M/F

011

24

52.0 ± 8.2

22/2

13

9

Group 2

23

54.0 ± 5.5

19/4

10

12

(IXC 25° C) Group 3

25

52.8 ± 7.1

23/2

13

9

Groups Group 1

I

Grafts/ pt.

Total XCT (min)

Duration of CPS (min)

2

EF(%)

NYHA Class

2

59.5 ± 16.8

2.3 ± 0.7

4.1 ± 0.4

40.1 ± 9.5

132.1 ± 21.0

59.1 ± 16.4

2.3 ± 0.7

4.6 ± 1.0

43.3 ± 11.1

145.7 ± 19.0

65.2 ± 13.0

2.5 ± 0.8

4.4 ± 0.9

63.3 ± 13.9*

148.0t ± 23.0

(IXC 32° C)

3

(cardioplegia) Legend: Values are mean ± standard deviation. IXC, Intermittent cross-clamping. Preop. MI, Number of patients with no, one, or two (0, 1,2) myocardial infarctions before operation. EF, Ejection fraction determind from the preoperative angiogram; the range is indicated between brackets. NYHA, New York Heart Association. XCT. Aortic cross-clamping time. CPB, Cardiopulmonary bypass. 'Group 3 versus Group 1 and Group 2 (p tGroup 3 versus Group 1 (p < 0.05).

< 0.01).

was reinfused until a septal temperature of less than 15 0 C was reached. All distal anastomoses were performed before release of the clamp. After the patient was rewarmed to a rectal temperature of 35 0 C but before cessation of CPB, another pair of "postischemic" biopsy specimens was taken from the same area in all three groups. At the end of CPB, the fresh blood from the oxygenator was slowly transfused to the patient until a left ventricular filling pressure (left atrial pressure or pulmonary capillary wedge pressure) of 8 mm Hg was reached in patients with normal ventricular function or 8 to 10 mm Hg in patients with previous left dysfunction. During the first few minutes after cessation of CPB, no inotropic compound was given. Cannulas were removed and, if the circulation remained stable, protamine hydrochloride was given after 15 minutes. Baseline studies included the electrocardiogram, systemic blood pressure, mean right atrial pressure, mean pulmonary artery pressure, heart rate, left ventricular pressure, and maximum rate of rise of left ventricular pressure. All these parameters were continuously monitored throughout the study. Cardiac output was measured in at least triplicate by the Edwards 9520 thermodilution computer. Derived hemodynamic indices were calculated as follows: CI = CO/BSA (L . min-I. M-') LVSWI = SI X (MAP - PWP) X 0.0136 (g . m . m') where Cl = cardiac index, CO = cardiac output, BSA = body surface area, LVSWI = left ventricular stroke work index, SI = stroke index, MAP = mean arterial pressure, and PWP = pulmonary wedge pressure. Biochemical analysis. ATP, CP, and glycogen in myocardial tissue. The biopsy specimens were immediately (within 3 seconds) cooled in liquid nitrogen and stored at -80 0 C. Adeno-

sine triphosphate (ATP), creatine phosphate (CP), and glycogen contents were determined in the biopsy specimen as described before.' CP and ATP were analyzed with a fluorometric technique according to Drake." This method is a modification of the technique described by Lamprecht. 5 Enzyme release. At 15 minutes and 4, 6, 7, 8, and 9 hours postoperatively, venous blood samples were taken for serial serum determinations of CK-MB.6 For each patient, total enzyme release was determined by planimetry of the time-activity curve. Determination of plasma catecholamines. Venous blood samples were taken before the start of CPB and 15 minutes after cessation of CPB. The concentration of norepinephine and epinephrine was estimated in plasma by simultaneous single isotope radioenzymatic assay as described by Peuler and Johnson.' Electron microscopy. The preischemic and postischemic biopsy specimens were immersed in the cold fixative containing 3% glutaraldehyde, buffered to pH 7.4 with 0.09 mol potassium oxalate. The samples were further processed for electron microscopy as described before.' A Philips EM 300 electron microscope was used. Light microscopic examination was done on toluidine blue-stained semithin sections. Morphologic assessment of all biopsy specimens was made in blind fashion, always by the same investigator. Ultrastructural damage to the mitochondria was assessed semiquantitatively by the score system as described previously." In every specimen, 800 to 1,000 mitochondria, originating from different cells and selected at random, were scored. Statistical methods. Differences between the three groups were tested for significance by Tukey's multiple comparison method." A paired t test was used to compare preoperative and postoperative values. Propor-

Volume 88 Number 2

Intermittent cross-clamping versus cardioplegia

167

August, 1984

Table II. Myocardial tissue concentration (umol . gm:' dry weight) Adenosine triphosphate Preop. Group 1 (lXC 32° C) (n = 24) Group 2 (lXC 25° C) (n = 21) Group 3 (cardioplegia) (n = 24)

I

Creatine phosphate

Postop.

Preop.

14.6* ± 5.1

30.6 ±

22.2 ± 5.6

18.1t ± 5.7

16.3 ± 6.9

16.3:1: ± 5.9

19.1 ± 5.2

I

Glycogen

Postop.

I

Preop.

Postop.

8.4

156.0 ± 57.6

34.1 ± 11.1

33.1:1: ± 11.9

193.8 ± 49.0

119.0* ± 56.1

26.0 ± 12.6

29.8:1: ± 9.2

I71.5 ± 65.1

163.5:1: ± 70.5

8.5

26.1:1: ±

95.2* ± 51.2

Legend: Mean values ± standard deviation. For abbreviations see Table I. 'p < 0.01 versus preop. tp < 0.01 versus preop. :j:p > 0.05 versus preop.

Table

m. Plasma catecholamine concentrations Norepinephrine (ng . ml:') Preop.

Group 1 (lXC 32° C) (n = 17) Group 2 (lXC 25° C) (n = 14) Group 3 (cardioplegia) (n = 18)

0.72 ± 0.44 0.67 ± 0.28 0.68 ± 0.57

I

Epinephrine (ng . mi:']

Postop.

Preop.

2.28 *t ± 1.46 1.30:1: ± 0.80 1.49* ± 0.84

0.15 ± 0.18 0.11 ± 0.19 0.13 ± 0.13

I

POSlOp. 0.33§ ± 0.37 0.53 ± 0.74 0.65:1: ± 0.69 p <0.01

Legend: Values ore mean ± standard deviation. For abbreviations see Table I. 'p < 0.001 versus preop. tp < 0.005 versus postop. Group 2. :j:p < 0.01 versus preop. §p < 0.05 versus prcop.

tions were compared by either McNemar's test (paired case, i.e. comparison between preoperative and postoperative phases) or a 2 X 3 contingency table (differences between groups in preoperative and in postoperative phase, respectively). Contingency tables were also used for evaluating the sex distribution (2 X 3) and the distribution of preoperative infarction (3 X 3).10,11 The Anderson actuarial survival" and event-free curves were made with 100% follow-up. The survival curves include the cardiac and the noncardiac operative and late deaths. Event-free studies were made for the operative survivors, events being defmed as onset of new angina, silent myocardial infarction, or sudden death. Results Patients and groups. Clinical data of the patients and comparison between groups are given in Table I. Age, sex distribution, number of preoperative infarctions, ejection fraction, New York Heart Association class, and number of grafts per patient were not significantly different between groups. The cardioplegia group (Group 3) had a significantly longer total aortic cross-clamp time than the other two groups (p < 0.01) and a significantly longer duration of CPB than the normothermic group (p < 0.05).

Biochemical analysis. ATP, CP, and glycogen in myocardial tissue. Myocardial tissue content of high-energy phosphates and glycogen was determined in the preischemic and in the postischemic (reperfusion) biopsy specimens. After ischemia, tissue content of ATP decreased significantly to 76.4% of control in Group 1 (p < 0.(01) and to 85.3% in Group 2 (p < 0.02). ATP content did not change significantly in the cardioplegia group. No significant changes in CP could be observed. Glycogen decreased significantly to 61% in Group 1 and to 61.4% in Group 2 (p < 0.(01) but remained unaltered in the Group 3. Comparison between groups revealed that preoperatively both ATP (p < 0.01) and CP (p < 0.05) were significantly lower in Group 3 (cardioplegia) than in Group 2 (hypothermia). Postoperatively, however, those differences were no longer significant. Glycogen, on the other hand, was not different between groups preoperatively. Postoperatively, the cardioplegia group had a significantly higher glycogen content than the normothermic group (p < 0.01) and the hypothermic group (p < 0.05). The data are summarized in Table II. Enzyme release. In every patient, serum CK-MB

The Journal of Thoracic and Cardiovascular Surgery

1 6 8 Flameng et al.

PATIENTS WITHOUT CORONARY ARTERY DISEASE 80 ~

70

~

60

~

50

CL

40

~

30

o

I-

CONTROL (n =39)

~

1

10

o

~II

25 50 75100 1% NORMAL MITOCHONDRIA)

g <

70 60

:5

50

~

40

CL

CORONARY ARTERY DISEASE

NORMOTHERMIA

HYPOTHERMIA

CONTROL (n=20)

CONTROL (n=21)

CARDIOPLEGIA CONTROL (n =21)

--' 30

:! 12

:s

20 10

~

z

g < :5 CL

70 60

POSTREVASCULARISATION

POSTREVASCULARISATION

POSTREVASCULARISATION

50

l( 40 --' 30

:! l2

:s

20 10

~

Preop.

Heart rate (beats/min) Group I 24 77 23 Group 2 73 Group 3 25 75 MAP (mm Hg) Group I 24 87 23 Group 2 84 Group 3 25 79 Cardiac index (L . m" . rn") 2.20 Group I 23 Group 2 21 2.32 22 .2.29 Group 3 LV dp/dt max (mm Hg/sec) Group I 22 1094 16 1012 Group 2 Group 3 20 1007 PWP (mm Hg) Group I 21 8.4 Group 2 16 7.5 Group 3 16 6.8 LVSWI (gm . m . m") Group I 22 35.1 Group 2 21 37.4 Group 3 20 34.0

1111111!

PATIENTS WITH z

No.

""'"'

l2 20 i!-

Table IV. Hemodynamic recovery /5 min postop.

± 20 ± 15 ± 16

95 ± 14 93 ± 15* 88 ± 14*

± 15 ± 15 ± 12

71 ± 11* 66 ± 12* 65 ± 8*

± 0.59 ± 0.60 ± 0.72

2.78 ± 0.45t 2.55 ± 0.53 NS 2.80 ± 0.68*

± 314 ;t

471 ± 360

900 ± 229* 816 ± 242 NS 875 ± 258 NS

± 2.2 ± 3.1 ± 2.5

8.7 ± 2.6 NS 10.5 ± 3.5t 8.6 ± 2.5:j:

± 9.1 ± 12.9 ± 11.3

29.1 ± 8.3:j: 25.0 ± 5.6t 28.4 ± 7.2

Legend: Values are mean ± standard deviation. MAP. Mean aortic pressure. LV dp/dt max. Maximum rate of rise of left ventricular pressure. PWP. Pulmonary wedge pressure. LVSWI. Left ventricular stroke work index. NS. Not significant

'p < 0.01. < 0.001. :j:p < 0.05. tp

Fig 1. Frequency distribution of the percentage of normal mitochondria in transmural left ventricular biopsy specimens. Upper panel: Histogram in a control population of 39 patients with valve replacement but without coronary artery disease. Biopsy specimens were taken before aortic cross-clamping. Middle panel: Histograms from the specimens taken before cross-clamping (Control) in the three groups of patients undergoing aorta-coronary bypass grafting. Normothermia = Group I (32 0 C). Hypothermia = Group 2 (25 0 C). Cardioplegia = Group 3 (cardioplegia). These histograms differ significantly from the histogram depicted in the upper panel (chi square <
ease. isoenzyme was determined serially until 9 hours postoperatively. Total washout of the enzyme was determined by planimetry of the time-activity curve. Total release of CK-MB was very low in all groups: 143.5 ± 59.2 U . L -I • hr for group 1, 130.1 ± 55.5 U . L -I • hr for Group 2, and 140.8 ± 60.4 U . L- 1 • hr for Group 3.

There was no statistically significant difference between these values. The values of CK-MB release correspond with myocardial necrosis in approximately 1 gm of myocardial tissue. 13 Plasma catecholamine concentrations. The plasma concentrations of norepinephrine and epinephrine were measured before and 15 minutes after CPB. Before CPB, no significant differences were obtained between the three groups for either norepinephrine or epinephrine. In the post-CPB phase, differences in epinephrine levels remained insignificant. Norepiniphine concentration, however, was significantly higher in Group I than in Group 2 (p < 0.05). In all three groups a highly significant increase in norepinephrine levels was observed between pre-CPB and post-CPB phases (p < 0.001 in Groups 1 and 3 and p < 0.01 in Group 2. Concerning epinephrine levels, there was a significant increase only in Group I (p < 0.01) and Group 3 (p < 0.05). The results are summarized in Table III. Morphology. Light microscopic examination of the

Volume 88 Number 2 August, 1984

preischemic and postischemic samples showed structural signs of chronic ischemia in patients with reduced anterior wall motion. We l4 have described these lesions previously. They were not morphometrically quantified in this study because they are not related to acute ischemia. On the ultrastructural level, signs of severe ischemic or postischemic damage such as nuclear alterations, damage to the contractile system, and rupture of the sarcolemma were not found. Structural abnormalities related to mild ischemia, such as intracellular edema and alterations of the sarcolemma-glycocalix complex, were frequently seen in the postischemic samples, but they were not quantified. However, mitochondrial ultrastructure, which is considered to be a sensitive criterion to evaluate ischemic damage, was assessed semiquantitatively by a previously described score system," A mitochondrion was scored "normal" when the membranes and the cristae were intact and the matrix was dark and contained osmiophilic granules, which are typical for well-oxygenated cells. When these conditions were not fulfilled, the mitochondrion was scored "abnormal." No further grading of ischemic damage was made because the incidence of severe stages of damage was extremely low and did not add any information. No significant differences between groups were found either for control or for reperfusion biopsy specimens. In Group 1, the percentage of normal mitochondria remained unchanged: 55.6% ± 23.7% in control specimens versus 52.2% ± 26.9% in the postrevascularization specimens (p > 0.05). In Group 2 similar results were obtained: 57.8% ± 22.6% control versus 64.5% ± 20.1% postrevascularization (p > 0.05). In Group 3, however, a significant increase could be observed: 48.8% ± 26.5% control and 64.6% ± 22.7% postrevascularization (p < 0.01). In order to show that the- low percentage of normal mitochondria found in the control specimens is inherent in a patient population with significant coronary artery disease, we compared the distribution of the percentage of normal mitochondria in our population with that of a patient population without coronary heart disease. Because it is impossible to obtain biopsy specimens from normal human hearts, we used a population of 39 patients with valve disease and normal coronary angiograms. The same biopsy fixation and scoring system was used. Fig. 1 (upper panel) shows the histogram of this control population. The frequency distribution of this histogram is highly significantly different (chi' <0.001) from that obtained from control specimens of our three groups of patients with coronary heart disease

(middle panel).

Intermittent cross-elamping versus cardioplegia 1 6 9

LVSWI 40

(g.m.M- 2 j

38

D--O

IXC j20(

C>--
IX( 2S0 (

36 34 32 30 28 26 24 22 PRE

S'POST

lO'POST

1S'POST

PWP 10 (mmHgl 8

6 PRE

S'POST

10'POST

1S'POST

Fig. 2. Recovery of left ventricular stroke work index (LVSWl) at 5, 10, and 15 minutes after cessation of cardiopulmonary bypass. There is a better recovery in the cardioplegia group than in Group 2 (IXC 25 C). The functional recovery found in Group I (IXC 3r C) is probably related to higher plasma levels of catecholamines (see Table ill). PWP, Pulmonary wedge pressure. SEM, Standard error of the mean. 0

After revascularization (lower panel), the distributions of the normal mitochondria in Groups 1 and 2 remain significantly different from the control group (chf <0.001 and chi' <0.05, respectively), although in the latter a slight improvement can be noticed. In Group 3, however, the frequency distribution is no longer significantly different from that in patients without coronary heart disease. Recovery of hemodynamics. At 5, 10, and 15 minutes after cessation of CPB, the following hemodynamic parameters were studied: aortic pressure, heart rate, cardiac index, maximum rate of rise of left ventricular pressure, pulmonary wedge pressure and left ventricular stroke work index. The results are illustrated in Fig. 2 and listed in Table IV. None of the preischemic values differed significantly between groups. After cessation of CPB, heart rate increased and mean aortic pressure decreased to the same extent in all groups.

The Journal of

170

Flameng et al.

Thoracic and Cardiovascular Surgery

Table V. Incidence of rhythm disturbances Group I (IXC 32" C) (n = 24) Preop.

Atrial fibrillation Atrial flutter Right bundle branch block Left bundle branch block Transient atrioventricular junctional rhythm Atrioventricular block without pacing Atrioventricular block with pacing Total Permanent atrioventricular block with pacing Ventricular extrasystolic beats Ventricular fibrillation

o

I

Group 2 (IXC 25" C) (n = 23)

Postop.

Preop.

2

o

o

2

2 3

3

2

o

o

o

S*

o o

o

S*

o

o o o

o I I

o

I

2t

o o

Preop. I

o

I

Postop.

o

o

3:1:

o o

2 I I

4

o

S*

o I

o

4* 12§ I

o

o

I

o

It

Postop.

o

o

o

I

Group 3 (cardioplegia) (n = 25)

o o

o

I

3

I:j:

*p < 0.05 versus preop. t Ineluding one patient with fatal acute myocardial infarction postop. :j:lneluding one patient with nonfatal acute myocardial infarction postop. §p

< 0.001 versus preop.

Cardiac index rose significantly after bypass in Groups 1 and 3 (p < 0.01), but not in Group 2. Maximum rate of rise of left ventricular pressure decreased significantly only in Group 1. (p < 0.01). Left ventricular stroke work index remained significantly depressed in both cross-clamp groups (Groups 1 and 2) 15 minutes after weaning from bypass (p < 0.05 and p < 0.001), not in the cardioplegia group (Group 3). At this point, recovery of left ventricular stroke work index was lowest in Group 2, only 67%, versus 82% in Group 1. In the cardioplegia group, the recovery rate of left ventricular stroke work index was 84%. Pulmonary wedge pressure was slightly but significantly increased after bypass in Group 2 (p < 0.001) and Group 3 (p < 0.05). In every group, two patients needed positive inotropic support with dopamine (3 to 7 ~g/min) after weaning from bypass. Low cardiac output was related to the preoperative ejection fraction: The two patients in Group 1 had an ejection fraction of 13% and 53%; those in Group 2, 21% and 48%; in Group 3, one patient had an ejection fraction of 45% and the other had an intraoperative acute anterior infarction. Clinical outcome. Incidence of myocardial infarction. The diagnosis of intraoperative myocardial infarction was accepted when the total CK-MB release within the first 9 hours postoperatively exceeded the mean CK-MB release in

the whole population plus two standard deviations of the mean. The incidence was 1/24 in the Group 1, 1/23 in Group 2, and 2/25 in Group 3. The patient in Group 2 was asymptomatic and the electrocardiogram did not indicate infarction. The patient in Group 2 and those in the Group 3 were also asymptomatic, but all had abnormal electrocardiograms. The incidence of myocardial infarction was not different between groups (p > 0.05). During the further postoperative course, i.e., more than 9 hours postoperatively in the intensive care unit, one additional acute myocardial infarction developed in every group. The diagnosis was made electrocardiographically. In Group 1, one patient had a massive acute infarction resulting from early graft failure after endarterectomy of the right coronary artery. The infarction was fatal because of irreversible low output. In Group 2, the additional infarction was asymptomatic. In Group 3, the additional infarction, resulting from early graft failure, was nonfatal but the patient needed positive inotropic support. Incidence of low cardiac output. Low cardiac output in the intensive care unit was defmed as the need for positive inotropic support, i.e., more than 4 ~g of dopamine per minute for at least 12 hours. In Group I, three of 24 patients (12.5%) needed positive inotropic support, in Group 2, two of 23 (8.7%), and in Group 3, two of 25 (8.0%). The incidence of low output was not

Volume 88

Intermittent cross-elamping versus cardioplegia

Number 2 August, 1984

O'Oh O'Oh

o/O~

"0 10 0 >

.;

~

100

90

100

90

80

90

80

86.8

t7.0

17 1

80

95.6 t4.3

91.4 t5.8

86.4 t7.3

1:

1

I

I

6

12

I

18 months

NORMOTHERMIA

~

1

I

I

6

12

I

18 months

HYPOTHERMIA

6

12 18 months

CARDIOPLEGI A

Anderson actuarial curves t one standard error

Fig. 3. Anderson actuarial survival and event-free curves of the three groups after 18 months' follow-up. Normothermia = Group 1 (32 0 C). Hypothermia = Group 2 (25 0 C). Cardioplegia = Group 3 (cardioplegia).

significantly different between the three groups. These patients are essentially the same as those who needed positive inotropic support after weaning from bypass. In Group 1, one additional patient had a low output syndrome 10 hours postoperatively. This was due to early graft failure after endarterectomy of the right coronary artery followed by an acute myocardial infarction. This patient's death was the only hospital death caused by cardiac disease in this study. The patient in Group 2 with an ejection fraction of 21%, who had a low output syndrome, needed intra-aortic balloon counterpulsation for 24 hours. Incidence of rhythm disturbances. The incidence of preoperative and postoperative rhythm disturbances is summarized in Table V. The incidence of new episodes of transient atrioventricular junctional rhythm and atrioventricular block, occurring early postoperatively or in the intensive care unit, was significantly increased in all groups (p < 0.05). The highest incidence of new atrioventricular conduction disturbances was found in the cardioplegia group (11/24 = 46%). In this group, four patients needed cardiac pacing because of total atrioventricular block. Follow-up. An Anderson actuarial survival study and an Anderson actuarial event-free study were made of the three groups (see Fig. 3). The mean duration of follow-up was similar: 21.4 ± 4.7 months for Group 1, 22.5 ± 3.0 months for Group 2, and 21.0 ± 4.7 months for Group 3. The cumulative actuarial survival rate for Group 1 was 86.8% after 18 months; there was one operative

cardiac death, and two patients needed a repeat operation. The actuarial event-free curve of the survivors shows that 81.0% were event-free after a similar time interval. In the Group 2, the actuarial survival rate was 95.6% and the event-free rate 96.4% after 18 months. There was one operative noncardiac death in this group, and none of the patients needed a reoperation during the follow-up period. After 18 months in the cardioplegia group, the actuarial survival rate was 91.4% and the event-free rate 78.2%. There was one operative cardiac death in this group and one patient needed a reoperation. Late cardiac deaths occurred in one patient in Group 1, none in Group 2, and two in Group 3. Discussion

These results demonstrate that the myocardial protection provided by intermittent aortic cross-clamping is as good as that offered by the St. Thomas' Hospital cardioplegic solution during extensive revascularization procedures. In none of the groups studied could significant myocardial cell necrosis be demonstrated. Leakage of the cardiac-specific enzyme CK-MB, a sign of irreversible cell damage," was minimal in all groups and indicated cell death in only 1 gm of myocardial tissue." The small amount of necrosis is probably not entirely related to the insult of global ischemia but also to manipulation of the atria, defibrillation, and dissection of the coronary arteries. Furthermore, histologic examination of transmural left ventricular biopsy specimens did not show significant ischemic damage, even on the ultrastructural level.

The Journal of

17 2

Flameng et al.

Jennings and Reiner I6 described the biological changes occurring in ischemic myocytes when they pass through the phase of reversible to the phase of irreversible injury. The early phase of reversible injury is characterized mainly by biochemical alterations in the myocardium and has little repercussion on structure of the ischemic cells. This is exactly what we found in the normothermic and hypothermic intermittent crossclamping groups (Groups 1 and 2). Even after a significant period of reperfusion, myocardial tissue glycogen was lowered, indicating the conversion of aerobic metabolic pathways to anaerobic glycolysis during ischemia. Also, ATP and CP levels were decreased as a reflection of the onset of destruction of the adenine nucleotide pool. Comparable observations were obtained in the experimental animal by Levitsky and associates. 17 An unexpected finding in our study was that biochemical changes occurred to the same extent in the hypothermic group as in the normothermic group. A possible explanation may be the persisting fibrillation of the heart during the reperfusion periods in the hypothermic group. The ultrastructural findings are focused on mitochondrial alterations, because the structure of these cell organelles is very sensitive to ischemia." The histograms obtained from samples taken before cross-clamping show that we are dealing with myocardium of chronically ischemic patients. The fact that these pathological histograms do not improve after ischemia plus reperfusion (i.e., revascularization) in the normothermic cross-clamp group or only very slightly in the hypothermic cross-clamp group suggests a lack of protection. St. Thomas' cardioplegia was able to prevent these biologic changes induced by global ischemia. Even after longer periods of aortic cross-clamping (63 minutes), ATP, CP, and glycogen remained unchanged. Because of this optimal myocardial preservation combined with complete revascularization and reperfusion, we found evidence for an improvement of myocardial structural integrity: The percentage of normal mitochondria had increased significantly after the intervention as compared to the preoperative status. These metabolic and structural parameters correlated well with the functional recovery of the hearts after CPB. In the cardioplegia group, cardiac index was significantly higher 15 minutes after CPB than before, and left ventricular stroke work index was essentially unaltered. In contrast, in Group 2, cardiac index did not increase and left ventricular stroke work index decreased significantly to 64% of the preoperative value. Besides postischemic impairment of the myocardial energy potential, changes in diastolic proper-

Thoracic and Cardiovascular Surgery

ties of the left ventricle also may be responsible for the reduced functional recovery after intermittent aortic cross-clamping." In Group I, a depression of cardiac performance after operation was masked by an increase in plasma catecholamine levels (Table III). Although cardioplegia offers better intraoperative protection, this technique has some drawbacks: There was a higher incidence of rhythm disturbances after the operations, mainly atrioventricular conduction problems. Fortunately, most of these conduction problems do not persist, but one must be aware of them. Despite better protection of the high-energy phosphate pool and early myocardial function with the St. Thomas' cardioplegic solution, some surgeons may prefer the intermittent aortic cross-clamping technique for practical reasons.' Sizing of the length of the bypass grafts is easier when the heart is distended with blood under beating conditions. This is particularly true when sequential grafts are being constructed. In diffusely diseased vessels, finding the best spot to incise a coronary artery may be difficult. It may often be easier when the coronary arteries are filled with blood rather than with clear crystalloid solution. Several clinical studies have been based on routine determinations of cardiac enzymes. Electrocardiogramcriteria deaths suggested that hypothermic cardioplegia provides better intraoperative protection than intermittent cross-clamping with intermediate reperfusion.":" Conti and associates," in a randomized study using immediate changes in left ventricular stroke work index and release of serum CK-MB isoenzyme, demonstrated that cardiac function was well preserved with both techniques and that myocardial necrosis probably occurred less often in the cardioplegia group. Roberts and colleagues,' in a nonrandomized matched-pair analysis, studied perioperative scans of myocardium labeled with technetium 99 pyrophosphate plus enzymatic (CKMB and lactic dehydrogenase 1), electrocardiographic, and hemodynamic determinations and concluded that the perioperative incidence of myocardial damage and changes in ventricular performance were almost identical with the two techniques. We also found no difference in the incidence of perioperative infarction or low cardiac output and clinical outcome between intermittent aortic cross-clamping and cardioplegia. Clinical outcome included early (hospital) and late (18 months) cardiac mortality and the event-free period. We conclude from this study that intermittent aortic cross-clamping is as effective as cardioplegia in protecting the myocardium from necrosis induced by global ischemia. However, areas of reversible ischemic injury, reflected by biochemical and ultrastructural alterations

Volume 88 Number 2 August, 1984

and impaired functional recovery, were not as well protected by intermittent aortic cross-clamping as by St. Thomas' cardioplegia. The clinical outcome was essentially the same with the two techniques. Nevertheless, these conclusions are valid only for the surgical conditions described in this study and probably not for more extended periods of aortic cross-clamping. REFERENCES Stiles QR, Kirklin JW: Myocardial preservation symposium. J THORAC CARDIOVASC SURG 82:870-877, 1981 2 Roberts AJ, Sanders JH, Moran JM, Kaplan KJ, Lichtendal PR, Spies SM, Michaelis LL: Nonrandomized matched pair analysis of intermittent ischemic arrest versus potassium crystalloid cardioplegia during myocardial revascularization. Ann Thorac Surg 31:502-511, 1981 3 Flameng W, Van der Vusse GJ, Borgers M: Methods for assessing preservation techniques: Invasive methods, A Textbook of Clinical Cardioplegia, RM Engelman, S, Levitsky eds., London, 1982, Futura Publishing Co., pp 63-79 4 Drake AJ: Analysis of adenosine triphosphate and creatinine phosphate, Ph.D. thesis, University of London, 1980 5 Lamprecht W: Determination of adenosine triphosphate, Methods of Enzymatic Analysis, H Bergmeyer, ed., Heidelberg, 1974 Springer-Verla y 6 Mercer DW, Varat MA: Detection of cardiac specific creatine kinase isoenzyme in sera with normal or slightly increased total creatine kinase activity. Clin Chern 21:1088-1092, 1975 7 Peuler JD, Johnson JA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine, Life Sci 21:625-633, 1977 8 Flameng W, Borgers M, Daenen W, Stalpaert G: Ultrastructural and cytochemical correlates of myocardial protection by cardiac hypothermia in man. J THORAC CAR. DIOVASC SURG 79:413-424, 1980 9 Kleinbaum 00, Kuppen, LR: Applied Regression and Other Multivariable Methods, North Seimate, Mass., 1978, Duxburg Press 10 Steele RGD, Tovrie JH: Principles and Procedures of Statistics, With Special Reference to Biological Science, New York, 1966, McGraw-Hill Book Company, Inc.

Intermittent cross-elamping versus cardioplegia 1 7 3

II Armitage P: Statistical Methods in Medical Research, Oxford, 1971, Blackwell Scientific Publications 12 Anderson RP, Bonchek LI, Grunkemeier GL, Lambert LE, Starr A: The analysis and presentations of surgical results by actuarial methods. J Surg Res 16:224-230, 1974 13 Hermens WTh, Willems GM, Visser MP: Quantification of circulating proteins, Theory and Applications Based on Analysis of Plasma Protein Levels, The Hague, 1982, Martinus Neyhoff Publishers 14 Flameng W, Suy R, Schwarz F, Borgers M, Piessens J, Thone F, Van Ermen H, Degeest H: Ultrastructural correlates of left ventricular contraction abnormalities in patients with chronic ischemic heart disease. Am Heart J 102:846-857, 1981 15 Shell WE, Sobel BE: Biochemical markers of ischemic injury. Circulation 53:Suppl 1:98, 1978 16 Jennings RB, Reimer KA: Lethal myocardial ischemic injury. Am J Pathol 102:241-255, 1981 17 Levitsky S, Wright RN, Rao KS, Holland C, Roper K, Engelman R, Feinberg H: Does intermittent coronary perfusion offer greater myocardial protection than continuous aortic cross-clamping? Surgery 82:51-59, 1977 18 Meessen H: Ultrastructure of the myocardicum. Its significance in myocardial disease. Am J Cardiol 22:319-327, 1968 19 Chitwood WR, Hill RC, Sink JD, Wechsler AS; Diastolic ventricular properties in patients during coronary revascularization. Intermittent ischemic arrest versus cardioplegia. J THORAC CARDIOVASC SURG 85:595-605, 1983 20 Conti VR, Bertranou EG, Blackstone EH, Kirklin JW, Digemess SB: Cold cardioplegia versus hypothermia for myocardial protection. J THORAC CARDIOVASC SURG 76:577-589, 1978 21 Adappa MG, Jacobson LB, Hetzer R, Hill JD, Kamm B, Kerth WJ: Cold hyperkalemic cardiac arrest versus intermittent aortic cross-clamping and topical hypothermia for coronary bypass surgery. J THORAC CARDIOVASC SURG 75: 171-178, 1978 22 Phillips SJ, Zeff RH, Kongtahworn C, Iannone LA, Brown TM, Gordon DF: Anoxic hypothermic cardioplegia compared to intermittent anoxic fibrillatory cardiac arrest. Clinical and metabolic experience with 1080 patients. Ann Surg 190:80-83, 1979