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Three Part Question

For [patients undergoing CABG at higher risk of stroke] is the [single-cross clamp technique] of benefit in reducing the [incidence of stroke]?

Clinical Scenario

Your consultant is about to operate on an urgent in-patient referral with left main stem disease who has long-standing diabetes and hypertension with atheromatous changes in the aorta. You ask him if he will use the single cross-clamp (SC) technique for coronary artery bypass grafting (CABG). He replies that he has not seen any convincing papers that prove that this will protect the patient from stroke and he is concerned that this technique may unnecessarily increase the myocardial ischaemic cross-clamp time. You decide to look up the evidence for his statement.

Search Strategy

The English language scientific literature was reviewed primarily by searching Medline from 1950 through November 2007 using Ovid interface.

cross-clamp.mp OR crossclamp.mp] AND [CABG.mp OR exp Thoracic surgery OR Coronary art$ bypass.mp OR Cardiopulmonary bypass.mp OR exp Cardiovascular surgical procedures OR exp Thoracic surgical procedures OR exp Coronary artery bypass] AND [exp stroke OR stroke.mp OR mortality.mp or exp mortality].

The ‘related articles’ function was used to broaden the search and all abstracts, studies, and citations scanned were reviewed. The reference lists of articles found through these searches were also reviewed for relevant articles.

Search Outcome

A total of 458 papers were found using the search strategy and only randomised controlled trials (RCTs) were selected. Six RCTs, of which one was a duplicate publication, were deemed to represent the best evidence on the topic and are summarised in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hammon et al 2007, USA	237 high-risk patients undergoing elective CABG. Of these 107 patients who had NP testing at all four periods (preop, at 1 week, 6 weeks and 6 months) were analysed. These were randomised to SC group (n=54) and MC group (n=27) and compared with 26 patients undergoing OPCAB	RCT (level 1b)	Incidence of stroke	Similar, MC group 2, OPCAB 1, SC group 2	Less than half of the available patients underwent neurological testing Patients with a grade 5 atheromatous aorta were excluded from randomisation Patients with neurodegenerative disease, major depressive disorder within the last 5 years, class IV congestive heart failure, cirrhosis, renal failure with creatinine 1.8 mg/dl, or any other serious life-threatening disease were excluded. Inclusion of OPCAB group potential confounder Small sample size resulting in lack of statistical power. Hypothermia could account for some differences
			11-part NP examination at 6 months postoperatively	Significantly more MC and OPCAB patients had NP deficits (P=0.067). MC 26%, OPCAB 27%, SC 9%
Tsang et al, 2003, Canada	268 consecutive patients undergoing elective CABG were randomised to SC group (n=134) and MC group (n=134)	RCT (level 1b)	Incidence of stroke and postop confusion	More in MC group (relative risk =2.0, P<0.05). SC 0, MC 2 (1.5%) and 2 (1.5%)	Short-term follow-up. No neuropsychological testing done. Two patients randomised to MC were switched to SC intraoperatively because of severe calcification of the ascending aorta.
			Incidence of perioperative MI	Similar (P=0.50). SC group 3 (2.3%), MC 2(1.5%)
			Incidence of mortality	Similar (P=0.50). SC group 2 (1.5%), MC 3 (2.2%)
Dar et al, 2001, UK	50 consecutive patients undergoing elective, isolated, primary CABG were randomised to SC group (n=25) and MC group (n=25)	RCT (level 1b)	Incidence of stroke	NIL in both groups	Patients with history of cerebrovascular disease, carotid bruit, aortic calcification, atrial fibrillatioin, or age more than 75 years were excluded. One patient in MC group was excluded because control S-100 levels were higher than postoperative Small sample size
			Serum S-100 protein levels	Significantly higher in MC group than in SC group (P<0.015). SC 0.67 µg/l, (IQR, 0.40–0.84 µg/L), MC 0.98 µg/l, (IQR, 0.61–1.11 µg/l)
			Serum troponin T levels	Similar. SC 0.62 µg/l, (IQR 0.3–1.09 µg/l), MC 0.50 µg/l (IQR 0.35–1.09 µg/l)
Musumeci et al, 1998, UK	91 patients with stable angina undergoing elective CABG were prospectively randomised ti IIA group (n=43) or SC group with intermittent anterograde cold blood cardioplegia	RCT (level 1b)	Incidence of stroke	Similar. IIA group 0, SC group 1.	Patients with a history of cerebrovascular disease, carotid bruit, aortic calcification, atrial fibrillation were excluded Small sample size Patients with unstable angina excluded. Different myocardial protection strategies used.
			Intraoperative cerebral microemboli	Similar. The median number of ME detected per patient was 34 (range 4-208). IIA group 34/patient, SC group 34.5/patient
			Serum S-100 levels	Similar except in one patient with SC who had an operative stroke. IIA group <0.2 µg/l, SC group <0.2 µg/l
			LNNB scores	Similar
			New Q waves	Signifcant in SC group (P=0.044)
			Serum CK-MB levels	Similar
			Serum troponin-I levels	Similar
			Serum troponin-T levels	Significant increase (P<0.03), IIA group 0.8 µg/l, SC group 1.08 µg/l
			LVWM score index	Similar. IIA group Increased from 1.35±0.50–1.73±0.50. SC group Increased from 1.22±0.26–1.74±0.37
Bertolini et al, 1997, Italy	100 patients undergoing elective CABG were randomised to MC group (n=55) or SC group (n=45)	RCT (level 1b)	Incidence of stroke	Similar. MC group 3 (5.4%), SC group 0	Unstable angina, emergency procedures, reoperations and preoperative counterpulsation accounted for a higher risk score in SC patients (P<0.03) Crystalloid cardioplegia used in MC group while blood cardioplegia used in SC group as myocardial protection strategy Small sample size
			Incidence of MI	Similar. MC group 6 (11%), SC group 2 (4.4%)
			Incidence of renal failure	Similar. MC group 2 (3.6%), SC group 0
			Hospital mortality	Similar. MC group 1 (5.5%), SC group 0
			Analysis of combined mortality and morbidity events (adverse events) between the two groups	Significant prevalence in MC group patients (P<0.03)

Comment(s)

Hammon et al. (2007) in a recently published randomised controlled trial (RCT), recruiting high-risk CABG patients divided into multiple clamp (MC) group (n=27) and SC group (n=54) and compared to an additional contemporary group of patients treated with off-pump CABG (n=26), showed that at six months, 26% of 27 MC patients had neuropsychological deficits, 27% of 26 off-pump CABG patients had neuropsychological deficits, and only 9% of 54 SC patients had neuropsychological deficits (P=0.067 vs. MC and off-pump CABG). The authors had published similar results previously as well (2006).

Tsang et al. in another RCT recruiting two hundred and sixty-eight consecutive patients undergoing CABG, randomised to MC group (n=134) and SC group (n=134), showed that there were no differences in the number of perioperative myocardial infarctions (Group SC=3 [2.3%]; Group MC=2 [1.5%], P=0.50) or mortality (Group SC=2 [1.5%]; Group MC=3 [2.2%], P=0.50). Two patients randomised to MC were switched to SC intraoperatively because of severe calcification of the ascending aorta. In Group MC, there were two strokes (1.5%) and two (1.5%) postoperative confusions vs. none in Group SC (relative risk=2.0, P<0.05, respectively).

Dar et al. in their RCT recruiting 50 consecutive patients undergoing elective, isolated, primary CABG showed that postoperative S-100 levels were significantly higher in MC group (n=24) than in SC group (n=25) (P<0.015) with no significant difference between the groups in postoperative troponin-T levels. One patient in MC group was excluded because control S-100 levels were higher than postoperative.

Musumeci et al. in their RCT comparing intermittent ischaemic arrest (IIA) (n=43) or SC with intermittent anterograde cold blood cardioplegia (n=48) showed that during elective CABG in patients with no clinical evidence of aortic or cerebro-vascular disease the incidence of peri-operative cerebral microemboli and postoperative neuropsychological disturbances are comparable with both techniques of myocardial preservation. However, median peak troponin I levels were 0.64 µg/l with IIA vs. 0.87 µg/l with SC (P=ns) and troponin T 0.8 µg/l vs. 1.08 µg/l (P<0.03).

Bertolini et al. in their RCT randomised CABG patients into two groups. In Group I, 55 patients underwent CABG using crystalloid cardioplegia and the conventional partial occluding clamp technique to perform proximal anastomoses, whereas in Group II, 45 patients were operated on combining blood cardioplegia and the SC technique. Analysis of combined mortality and morbidity events (adverse events) between the two groups, led to a significant prevalence in Group I patients (P<0.03) in spite of a higher preoperative risk score (P<0.03) and longer ischaemic times (P<0.001) in Group II patients. Moreover, neurological lesions remained confined to Group I patients.

Use of SC technique by avoiding repeated aortic manipulation appears a rational strategy to avoid neurological complications especially in high-risk patients with atheromatous aorta. Interestingly, all the RCTs, except Tsang et al. failed to show a superiority of this technique in reducing the incidence of postoperative stroke. This is mainly due to the multifactorial aetiology of postoperative stroke. Aortic cannulation/decannulation, punching aorta for construction of proximal anastomoses, inadequate deairing strategies are some of the major reasons leading to postoperative stroke apart from cross-clamp application/removal. Perhaps OPCAB ‘no-touch aorta’ total arterial revascularisation could be the ideal technique for avoiding postoperative stroke as it would theoretically avoid generation of micro- as well as macroemboli resulting from the use of cardiopulmonary bypass, aortic manipulation and inadequate deairing.

As for the limitations of the studies included in this BET none provide details about the aetiology of stroke. More importantly, the sample sizes are not adequate to reach statistical significance and last, but not the least, patients at highest risk of stroke were excluded from all trials.

Editor Comment

RCT, randomised controlled trial; SC, single aortic cross-clamp; MC, multiple aortic cross-clamp or partial occluding clamp technique; CABG, coronary artery bypass grafting; OPCAB, off-pump coronary artery bypass grafting; IQR, interquartile range; MI, myocardial infarction; CK-MB, myocardial isoenzyme of serum creatine kinase; IIA, intermittent ischaemic arrest; ME, microemboli; LNNB, Luria Nebraska Neuropsychological Battery; LVWM, left ventricle wall motion; NP, neuropsychologic.

Clinical Bottom Line

We conclude that current best available evidence, from six RCTs randomising 490 patients, suggests that there is no benefit of SC technique over MC technique in terms of reduction in the incidence of stroke (SC=2/206 vs. MC= 7/284; P=ns) although there is some advantage of SC technique in causing less neuropsychological deficits and release of serum S-100 protein, a surrogate marker of cerebral injury.

References

1. Hammon JW, Stump DA, Butterworth JF et al. Coronary artery bypass grafting with single cross-clamp results in fewer persistent neuropsychological deficits than multiple clamp or off-pump coronary artery bypass grafting. Ann Thorac Surg 2007;84:1174–1178.
2. Hammon JW, Stump DA, Butterworth JF et al. Single crossclamp improves 6-month cognitive outcome in high-risk coronary bypass patients: the effect of reduced aortic manipulation. J Thorac Cardiovasc Surg 2006;131:114–121.
3. Tsang JC, Morin JF, Tchervenkov CI et al. Single aortic clamp versus partial occluding clamp technique for cerebral protection during coronary artery bypass: a randomized prospective trial. J Card Surg 2003;18:158–163.
4. Dar MI, Gillott T, Ciulli F et al. Single aortic cross-clamp technique reduces S-100 release after coronary artery surgery. Ann Thorac Surg 2001;71:794–796.
5. Musumeci F, Feccia M, MacCarthy PA et al. Prospective randomized trial of single clamp technique versus intermittent ischaemic arrest: myocardial and neurological outcome. Eur J Cardiothorac Surg 1998;13:702–709.
6. Bertolini P, Santini F, Montalbano G et al. Single aortic cross-clamp technique in coronary surgery: a prospective randomized study. Eur J Cardiothorac Surg 1997;12:413–418.