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Eur J Cardiothorac Surg 1998;13:702-709
© 1998 Elsevier Science NL
Department of Cardiac Surgery and Cardiology, University Hospital of Wales, Heath Park, Cardiff CF4 4XW, UK
Received 8 December 1997; received in revised form 2 March 1998; accepted 18 March 1998.
Corresponding author. Tel.: +44 1222 743889; fax: +44 1222 744744.
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Abstract |
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 Top Abstract Introduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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Key Words: Coronary artery surgery • Myocardial protection • Cardioplegia • Cerebral dysfunction • Transcranial Doppler
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Introduction |
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TopAbstractIntroduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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Equally important for a successful outcome of coronary artery surgery is to minimize the risks of post-operative cerebral dysfunction which may be determined by the surgical technique used [4] or the direction of cardioplegia delivery [5].
In recent years, the use of intermittent ischaemic arrest for myocardial preservation has been readvocated for its simplicity and prospective randomized clinical trials have demonstrated that it provides equivalent or better myocardial protection than cold cardioplegia [6] [7]. The technique of intermittent ischaemic arrest is, however, associated with repeated manipulation of the aorta with repetitive clamping and partial occlusion. The repeated aortic trauma may result in debris from the aortic wall being shed into the systemic circulation.
Increased aortic manipulation during coronary artery bypass surgery is known to be associated with embolic events, particularly in patients with atherosclerotic disease of the ascending aorta [4]. Cerebral microemboli occurring during surgery can be detected non-invasively by peri-operative transcranial Doppler monitoring. These events have been associated with clinical neurological dysfunction after the operation [8] [9]. The use of the single cross-clamp technique has, therefore, been advocated as it involves minimal handling of the aorta and has been reported to reduce the incidence of adverse neurological events post-operatively [4].
In this study we explored the hypothesis that intermittent ischaemic arrest may provide better myocardial preservation due to the shorter ischaemic time, but may generate a larger number of cerebral microemboli and consequently a higher incidence of post-operative cerebral dysfunction compared to the single cross-clamp technique.
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Material and methods |
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TopAbstractIntroduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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Clinical criteria for patients to be prospectively considered eligible for the study were haemodynamic stability, stable angina, a minimum of 3 months since myocardial infarction, and no history of neurological disease or psychiatric illness and no clinical evidence of carotid and peripheral vascular disease. Patients with renal impairment (creatinine >150 µmol/l) or abnormal liver function (liver enzymes greater than twice the normal range) were excluded. Additional inclusion criteria were literacy, agreement to participate in the study, lack of visual, auditory or speech deficits, and adequate physical health to complete the battery of neuropsychological tests.
Anaesthesia and operative management
In all patients anaesthesia was induced with etomidate (0.2–0.3 mg/kg) or propofol (2 mg/kg). Fentanyl (15–20 µg/kg) was used for analgesia. Neuromuscular blockade was achieved with pancuronium (0.1 mg/kg.) or vecuronium (0.1–0.2 mg/kg). Anaesthesia was maintained with isoflurane or propofol.
The perfusion circuit consisted of a custom made tubing pack (Sorin Biomedica UK Ltd., Midhurst, UK) containing a Monolyth membrane oxygenator and a 40 µm blood arterial line filter (Sorin Biomedica Cardio, Saluggia, Italy). The circuit was primed with 1500 ml of Plasmalyte 148 solution (Baxter Healthcare, UK).
Cardiopulmonary bypass was performed with non-pulsatile flow and the flow rate was adjusted according to the body temperature. For the IIA group the body temperature was allowed to drift to 34°C and the flow rate maintained at 2.4 l/m2 per min whilst in the SCT group the temperature was actively reduced to 28°C and the flow decreased to 1.6 l/m2 per min. The pH-stat method of acid-base balance was used throughout the course of cardiopulmonary bypass. The mean arterial pressure was maintained between 50 and 75 mmHg.
In patients randomized to IIA, the distal anastomoses were performed during brief periods (approximately 10–15 min) of total aortic occlusion and induced ventricular fibrillation. On completion of each distal anastomosis the aortic clamp was released. If the heart did not defibrillate spontaneously, a 10–20 J direct current was used. The proximal anastomosis was then performed after isolation of a portion of ascending aorta by applying a side-biting clamp. This sequence was repeated according to the number of grafts required. No venting of the left ventricle or the aortic root was used.
With the SCT, proximal anastomoses were sequentially constructed after each distal anastomosis during a single cross-clamp period. The heart was arrested with 1 l infusion of high potassium (20 mEquiv./l) anterograde cold (4–8°C) oxygenated blood cardioplegia (4:1 blood/Buckberg's solution). Further doses, with a lower potassium concentration (10 mEquiv./l), were delivered at a rate of 200 ml/min over 2 min at 15-20-min intervals, after the completion of each proximal anastomoses. The aortic root and the vein grafts were carefully de-aired before tying the sutures.
In the cardiac surgical intensive care unit a standardized protocol for weaning from assisted ventilation was followed.
Assessment of myocardial preservation
The efficacy of myocardial preservation during surgery was assessed by serial measurements of serum cardiac specific enzymes, and from pre- and post-operative electrocardiographic changes, and cross-sectional echocardiographic changes in left ventricular function.
Biochemistry
Blood samples for measurements of Troponin T (TnT), Troponin I (TnI) and Creatine Kinase (CK) and CK-MB isoenzyme were collected pre-operatively and at 10, 24 and 96 h post-operatively. TnT was assayed using the Boehringer Mannheim, Enzymun system assay, TnI by the Pasteur kit, and CK-MB by the Ciba-Corning CK-MB assay.
Electrocardiography
Electrocardiograms were recorded before surgery, at discharge and at 6 months follow-up. The development of a new Q wave (>0.04 ms) or loss of >25% of R waves in at least two leads were considered diagnostic of peri-operative myocardial infarction. ST-T wave changes were also recorded as were post-operative atrial arrhythmias.
Echocardiography
Left ventricular function was assessed the day before surgery, prior to hospital discharge and 6 months post-operatively by trans-thoracic cross-sectional echocardiography using a Hewlett-Packard Sonos 1500 machine with a 2.5 MHz probe. Each study recorded standard parasternal long and short-axis views and apical four and two chamber views. The left ventricular wall was divided into 16 segments and a wall motion score was assigned to each segment using the Herman and Gorlin scoring system: normal=1, mild or moderate hypokinesia=2, severe hypokinesia or akinesia=3, dyskinesia=4, aneurysmal=5. A total score was obtained by adding the score for each segment that could be visualized and a left ventricular wall motion score index calculated by dividing the total score by the number of segments visualized
[10]. Echocardiograms were analysed in a blinded fashion by independent investigators who were unaware of the operative details.
Assessment of neuropsychological outcome
Intra-operative cerebral microemboli (ME) were counted by continuous transcranial Doppler recording of the blood flow velocity in the right middle cerebral artery and correlated with surgical events. A detailed neuropsychological assessment was performed pre and post-operatively using the Luria Nebraska Neuropsychological Battery (LNNB). Circulating levels of serum protein S-100, a specific marker of cerebral injury, were also measured pre- and post-operatively.
Transcranial Doppler technique
A TC2020 Pioneer transcranial Doppler (TCD) machine (EME, a Nicolet Company) with a 2 MHz probe was used to continuously record blood velocities from the right middle cerebral artery during surgery. The probe was positioned in front of the right ear above the zygomatic arch (trans-temporal window) and care was taken to adjust the orientation and depth of the Doppler signals to obtain the best signal strength possible. The probe was held in place by a head band. The machine setting was kept constant for all patients (power 58%; sweep speed 6; depth of insonation 46–56 mm). All emboli, whether solid or gaseous produced a readily audible frequency response (>9 dB) above the background Doppler blood velocity spectrum with a particular `chirp' sound and showed as an instant bright-red, unidirectional high-velocity signal on the screen (duration of <0.15 s for systolic signals and <0.3 s for diastolic signals)
[11]. Embolic signals were detected in real time by the TCD operator and stored using the automatic installed detection software (version 2.00 Pioneer Software) which was activated during the recordings for later review. Microemboli were counted using the criteria published by Spencer
[12] and recorded from the time of aortic cannulation to aortic decannulation. Events were labelled as `spontaneous', when not related to surgical manoeuvres, or as `surgical', when related to surgical manipulations such as aortic cannula insertion, starting CPB, cardiac manipulation, partial or total aortic clamping and declamping, defibrillation, cardiac manipulation and decannulation.
Neuropsychologic testing
Form I of the LNNB was selected to assess motor function (motor speed, gross motor activity, verbal direction of motor movement, presence of motor preservation and oral motor skills),visual function (perceptual skills), reading, memory (verbal and non-verbal short-term memory), and intellectual process (integrity of intellectual functions and tasks requiring complex reasoning and problem solving skills)
[13]. All patients completed the baseline neuropsychological assessment on the day prior to surgery, before discharge and 6 months post-operatively. The patient was tested by a trained psychologist in a quiet room where lighting conditions could be kept constant and interruptions were prevented. A table was positioned in front of the patient and testing commenced only after clear identification was given that all instructions were understood.
Biochemistry
Serum concentration of the protein S-100 was measured by a monoclonal two-site immunoradiometric assay (Sangtec® 100, AB Sangtec Medical, Bromma, Sweden) before and at 10, 24, and 96 h after the end of cardiopulmonary bypass. Levels in excess of 0.2 µg/l were considered pathological
[14].
Statistical analysis
The statistical analysis was performed with the Statistical Package for Social Sciences Software (Analysis of variance, t-test, Mann–Whitney test). The Mann–Whitney test was used to compare the differences in median values of CK-MB, TnT, TnI levels and number of microemboli. The 
2-test was used to compare the difference in incidence of hypertension, smokers, previous myocardial infarction and left main stem disease in the two groups. When variables involved a small number of patients (diabetes, non-use of left internal mammary artery, presence post-operatively of new Q wave or ST anomalies), the Fisher exact test was used. Paired Student's t-test was used to compare age, cardiopulmonary bypass time, ischaemic time, median number of grafts, ITU stay, hospital stay, differences in pre- and post-operative mean echocardiographic scores and LNNB scores. Pearson's correlation coefficient was used to correlate pre- and post-operative variation in LNNB scores, total number of ME and technique of cardioplegia and also to correlate LNNB score, age and technique of cardioplegia. All continuous variables are expressed as mean value±standard deviation unless differently stated. All P values were two-tailed and values less than 0.05 were accepted as to indicate statistical significance.
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Results |
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TopAbstractIntroduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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Serum concentrations of CK-MB, TnT and TnI increased post-operatively in both groups even after excluding the four patients in the SCT group who developed Q waves post-operatively. The peak levels at 10 h, 24 h, 96 h post-operatively were higher in the SCT group compared to the IIA group. This difference reached statistical significance at 10 h post-operatively with CK-MB (P=0.021) and at 10 h and 24 h with TnT (P=0.038 and P=0.027, respectively) ( Fig. 1 ).
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Neuropsychological outcome
The total number of ME recorded per patient ranged from 4 to 208. The total number of ME was similar in the two groups and there was no difference in median number of ME per patient between the two groups (IIA=34 ME/patient, SCT=34.5 ME/patient, (P=NS)).
Fig. 2 shows the mean number of ME and their relationship to the surgical manoeuvres for the two techniques of myocardial preservation used. With IIA, ME occurred mainly during surgical manipulation, particularly at the time of total or partial aortic cross-clamping. Few spontaneous events were detected in this group, whereas in the SCT group most of the ME were spontaneous (P<0.01).
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Finally, no differences were found between younger patients (<65 years n=74) and older patients (>65 years (n=9 (20%) IIA, n=8 (16.6%) SCT) and neuropsychological outcome.
Circulating levels of the neuro-specific protein S-100 were in the normal range (<0.2 µg/l) for all patients at 10, 24 and 96 h post-operatively except for one patient who had a peri-operative stroke (0.9 µg/l at 10 h and 0.4 µg/l at 24 h).
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Discussion |
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TopAbstractIntroduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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The safety and effectiveness of intermittent ischaemic arrest has been demonstrated during elective coronary surgery as well as in higher risk patients [15] [16] and further endorsed by a number of prospective randomized clinical trials where intermittent ischaemic arrest has been compared to cold crystalloid [6] or blood [7] [17] cardioplegia. Pre-ischaemic preconditioning has been suggested as a possible protective mechanism for the myocardium [18]. Yellon et al. have given support to this hypothesis by demonstrating a better preservation of ATP content in the myocardium during subsequent periods of ischaemia during intermittent ischaemic arrest for coronary surgery [19]. Furthermore, with intermittent ischaemic arrest, the sequential construction of distal and proximal anastomosis allows increasing areas of myocardium to be re-perfused during the course of the operation. The same rationale applies to the single clamp technique. By sequentially performing distal and proximal anastomoses, a more homogeneous distribution of cardioplegia and myocardial cooling is provided while the aortic cross-clamp is in place and also homogeneous rewarming with maximal restoration of blood flow to ischaemic myocardium when the clamp is removed [4]. Despite a significant increase in cross-clamp time, improved results with the single cross-clamp technique compared with the traditional technique have been reported [4].
In our study, no difference was evident between the two techniques in hospital survival and in clinical outcome at 6 months follow-up. However, intermittent ischaemic arrest was associated with a significantly shorter hospital stay (P<0.05). ITU stay was also shorter although the difference did not reach significance. Intermittent ischaemic arrest was also associated with lower release of cardiac specific enzymes CK-MB, TnT and TnI, even when the four patients in the single clamp technique group who had a peri-operative myocardial infarction were excluded. With intermittent ischaemic arrest, lower post-operative serum level of CK-MB and TnT were found by Anderson et al. when the technique was prospectively compared to cold blood cardioplegia [7]. Gerola et al. failed to demonstrate any significant difference in release of cardiac enzymes between the two techniques [17], this, however, may be related to the shorter ischaemic time in patients in the intermittent ischaemic arrest group in our series.
We evaluated left ventricular systolic function non-invasively using trans-thoracic cross-sectional echocardiography applying a standard wall motion scoring system [10]. The main advantage of this methodology is its ability to recognize changes non-invasively for each given patient over a period of time and to provide a quantitative measure of any such changes for subsequent analysis. Deterioration in ventricular function from the pre-operative assessment was detected seven days post-operatively. However, at 6 months follow-up ventricular function had recovered. These changes occurred for both groups and there was no significant difference between them, although there was a tendency for initial deterioration to be less and late recovery greater when intermittent ischaemic arrest was used.
The second hypothesis we tested in this study was the impact of repetitive aortic handling during surgery on the generation of microemboli and its relation to neuropsychological outcome. Transcranial Doppler ultrasonography of the right middle cerebral artery is a well established technique for counting microemboli in the cerebral circulation during cardiopulmonary bypass [20] [21]. We detected no difference in the number of cerebral microemboli between the two techniques of myocardial preservation. However, the pattern of microemboli was different as previously reported by Clark et al. [9], in that during intermittent ischaemic arrest, microemboli mainly occurred at times of surgical manipulation particularly during total and partial aortic clamping whereas with the single clamp technique there was a continuous low grade production of microemboli with a large shower when the aortic cross-clamp was removed.
The median number of microemboli (n=34) occurring during surgery in our study was less than reported in many other studies [8] [9]. Clarke reported the occurrence of cerebral complications in 35% of patients who had >60 microemboli during surgery whilst only 3/107 patients with <60 microemboli developed any neurological sequelae [9]. Only one of our patients, in the single clamp technique group, had a post-operative stroke and none of the others had any clinical evidence of neurological dysfunction. We detected only a minor deterioration on neuropsychological testing 1 week post-operatively which recovered at 6 months follow up, interestingly to a level better than pre-operatively, probably due to the patient's lack of apprehension and anxiety which may have been present before surgery. These changes did not achieve statistical significance and were similar in both groups. An initial decline followed by improvement in cognitive function following coronary artery bypass grafting had been reported by other investigators [22] [23] and our findings confirm that minor changes in cognitive function after CABG are transient.
Previous studies have shown that the Luria Nebraska Neuropsychological Battery chosen for this study is a valid and reliable tool, sensitive enough to detect mild impairment accurately [13] [24]. The Luria Nebraska Neuropsychological Battery has been shown to be comparable to the Minnesota Multiphasic Personality Inventory, the Peabody Individual Achievement Test and the Wechsler Adult Intelligence Test Revised [25]. Each patient was assessed pre-operatively to get an accurate baseline against which to compare the post-operative results, as recommended by the consensus statement on neurological outcome after cardiac surgery [26]. The late improvement in Luria Nebraska Neuropsychological Battery score shown in our study supports the consensus panels advice that a further assessment should be made at least 3 months after surgery when performance is more stable [26].
We could find no evidence of neuropsychological impairment in our patients with higher microemboli counts probably due to the overall low level of microemboli in our series. Similarly, an analysis of variance showed no relationship between the method of myocardial protection, the total number of microemboli and the Luria Nebraska Neuropsychological Battery score.
Further evidence of a good neuropsychological outcome in our patients was the finding that circulating levels of the neuro specific protein S-100 at 10 and 24 h post-operatively was in the normal range in all cases except the one patient who had a CVA. Westaby has previously shown a persistent elevation in S-100 protein post-operatively in patients with major cerebral damage [27]. Transient elevations in S-100 protein, peaking at <2 h post-operatively and returning to baseline at 24 h have been reported following cardiac surgery [14] but it is not known if these transient rises are associated with an adverse neuropsychological outcome.
Evidence of cerebro-vascular disease (previous CVA, carotid bruits, etc.) is a major risk factor for stroke following coronary artery bypass surgery [22]. We were careful to exclude such patients from our study and this probably explains why our older patients (>65 years) did as well as those <65 years in terms of neuropsychological outcome unlike previous studies [22] [28] which have suggested that increasing age is a risk factor for peri-operative stroke. For the same reason our finding of a similar outcome with the two techniques of myocardial protection cannot be extrapolated to high risk patients.
In summary, we have shown that in patients undergoing elective coronary artery bypass surgery, on biochemical analysis, intermittent ischaemic arrest provides more effective myocardial preservation than the single cross-clamp technique. We have also shown that, in patients with no clinical evidence of aortic or cerebro-vascular disease, the repetitive handling of the aorta with intermittent ischaemic arrest is not associated with an excess of cerebral microemboli or with a worse neuropsychological outcome compared to the single cross-clamp technique.
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Acknowledgments |
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstractIntroduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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Dr Feccia: Yes, in our department we use predominantly intermittent ischaemic arrest. We have done another study, where intermittent ischaemic arrest was compared with St. Thomas cardioplegia and we found that intermittent ischaemic arrest was superior in terms of myocardial preservation.
Dr D. Taggart (Oxford, UK): I would like to make two comments. I use intermittent ischaemia and have done so for a long time. We have recently just completed a study in terms of myocardial protection. The reason I think it works better than cardioplegia is that you can demonstrate induction of heat shock protein acutely if you keep patients at 34°C and use intermittent ischaemia. If you use cold crystalloid cardioplegia you abolish induction of heat shock protein. So I think that may be the mechanism by which you have better myocardial protection. In terms of your neuropsychological tests, I think it was again a very good, clear study, and it would reiterate our own experience which I presented from Oxford. Basically using this technique of intermittent ischaemia, we found no difference in neuropsychological injury in those patients and in comparison to a group of patients undergoing coronary revascularization without bypass at all.
Dr A. Mazzucco (Verona, Italy): I saw your criteria for exclusion of patients from the study. I wonder, have you performed any echocardiographic scanning of the aortic wall preoperatively in order to define the status of the aortic wall? Because in our practice this has really been a matter of concern. And there is a good amount of patients in whom we would be rather reluctant to repeat several times aortic cross-clamping just because of the atheromatous modification of the aortic wall. So I suggest, if you have not done this, it could be a reasonable thing to do.
Dr Feccia: We did not assess pre-operatively the aortic wall by echocardiography but it was assessed by the surgeon in the operating room and we excluded patients who had significant atheroma.
Dr P. Bertolini (Verona, Italy): One of your exclusion criteria was unstable angina. Now, my question is, what is the actual policy for the treatment of such patients at your unit? Do you treat them with intermittent clamping, or rather switch them to the group with a single aortic cross-clamp time?
Dr Feccia: We use intermittent ischaemic arrest also for unstable angina patients but we excluded them from this study because changes in ECG and cardiac enzymes postoperatively may have been difficult to interpret.
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References |
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TopAbstractIntroduction
Material and methodsResultsDiscussion
Appendix A. Conference...References |
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This article has been cited by other articles:
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  L. Raco, E. Mills, and R. J.W. Millner Isolated myocardial revascularization with intermittent aortic cross-clamping: experience with 800 cases Ann. Thorac. Surg., May 1, 2002; 73(5): 1436 - 1439. [Abstract] [Full Text] [PDF]
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 R. Bessho and D. J. Chambers Myocardial protection: The efficacy of an ultra-short-acting {beta}-blocker, esmolol, as a cardioplegic agent J. Thorac. Cardiovasc. Surg., November 1, 2001; 122(5): 993 - 1003. [Abstract] [Full Text] [PDF]
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 R. W. Kim, D. C. Mariconda, G. Tellides, G. S. Kopf, M. L. Dewar, Z. Lin, and J. A. Elefteriades Single-clamp technique does not protect against cerebrovascular accident in coronary artery bypass grafting Eur. J. Cardiothorac. Surg., July 1, 2001; 20(1): 127 - 132. [Abstract] [Full Text] [PDF]
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R. Bessho and D. J. Chambers Experimental study of intermittent crossclamping with fibrillation and myocardial protection: Reduced injury from shorter cumulative ischemia or intrinsic protective effect? J. Thorac. Cardiovasc. Surg., September 1, 2000; 120(3): 528 - 537. [Abstract] [Full Text] [PDF]
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 P. S. Wong, S. Vendargon, C. G. Lim, P. S. Wong, S. Vendargon, and C. G. Lim Coronary Artery Bypass Surgery Without Cardioplegia: Early Results Asian Cardiovasc Thorac Ann, June 1, 2000; 8(2): 103 - 108. [Abstract] [Full Text] [PDF]
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