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Three Part Question

In [patients submitted to coronary artery bypass grafting], Is [Transit-Time flow measurement a useful method] To [achieve intraoperative graft verification] ?

Clinical Scenario

A 57 years old male complaining of unstable angina was submitted to single Left internal mammary artery (LIMA) to Left anterior descending (LAD) artery on-pump grafted distally to a twice stented, severe proximal stenosis. After weaning from Cardiopulmonary bypass (CPB), LIMA was judged well functioning on the basis of finger palpation. Ventricular tachicardia occurred before sternal closure and patient was transferred to intensive care unit under lidocaine infusion. Few hours later a low cardiac output syndrome with LIMA occlusion diagnosed at angiography led patient to emergent surgery.
On cardioplegic arrest LIMA was found totally dissected with LAD occlusion at proximal site of anastomosis. A saphenous vein graft was used to revascularize LAD. Intraortic Ballon Pumping was necessary to wean the patient. The anterior myocardial necrosis prolonged hospital stay.
On the basis of risk management protocol you carry on a literature survey in order to demonstrate clinical usefulness of Transit-Time flow measurement (TTFM) in coronary graft verification.

Search Strategy

Medline 1950 to December 2009 using the PUBMED interface and selecting MEDLINE from the Subsets menu on the limits screen.
"coronary artery bypass"[MeSH Terms] AND ("transit-time"[All Fields] OR "transit time flow measurement"[All Fields]) AND (intraoperative[All Fields] OR "graft revision"[All Fields] OR "graft patency"[All Fields] OR verification[All Fields]) AND medline[sb].

Search Outcome

Hundred and two papers were found, 10 of which were included in the BestBETs analysis reported below. The relevant papers are presented in Table 1. Level of evidence are assigned according to Oxford Center for Evidence-Based Medicine [2]

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Canver and Coll. Ann Thorac Surg 1994 USA	-63 patients submitted to isolated CABG using internal thoracic artery and saphenous vein grafts -TTFM used in all cases to compare direct measurement of ITA free flow in a beaker to TTF measurement. -TTFM used to compare ITA free flow to post CABG -Simultaneous measurement by means of two identical equipments of arterial and venous flow.	Retrospective cohort study (level 2b)	-TTFM validation compared to free bleeding measurement	a) no TTFM difference between on-pump and off-pump CABG	1)no data supporting Author’s statement concerning TTFM in vivo validation; 2)no data concerning flow parameters in 2 patients submitted to graft revision
			-OFF/ON PUMP MGF difference	b) no TTFM difference between arterial and venous grafts just before sternal closure
			to verify possible difference between arterial and venous grafts, either after on-pump or off-pump CABG.	c) in two patients TTFM prompted graft correction with clinical improvement
D’Ancona and Coll. 1999 USA	-161 patients submitted to OFF-PUMP CABG with a total of 323 grafts: 183 grafts to the anterior wall (LAD and D) 60 to the lateral wall (circumflex or marginal) 75 to the posterior wall (RCA or PDA) 5 to other minor coronary branches. -All grafts tested with TTFM	Retrospective cohort study (level 2b)	-To evaluate if TTFM can improve the quality of information and increases the accuracy of diagnosing technical problems in bypass grafts	32 grafts (9.9%) surgically revised based on	-Absence of control group with a gold standard of grafts verification -Clinical efficacy based only on the findings at graft revision,
				All revised grafts were found to have a significant
				No major complications, myocardial infarctions, or
Leong and Coll. 2005 Singapore	-116 patients underwent isolated CABG grafting. • 67 patients on-pump CABG • 49 patients off-pump CABG -125 arterial and 197 vein grafts. -Transit-time flow measurement was carried out on all completed grafts. -Graft patency was assessed using flow curves, MGF and PI.	Retrospective cohort study (level 2b)	TTFM ability to detect technical errors in grafts.	-6 patients had 7 grafts revised for high PI, low MGF, unsatisfactory flow curve, or all of them	-Absence of control group with a gold standard of grafts verification. -Clinical efficacy based only on the findings at the graft revision.
				MGF significantly increased after correction from 5.4 ± 3.7 mL/min to 26.4 ± 8.2 mL/min (p < 0.05).
				PI significantly decreased after correction from 11.3 ± 5.9 to 3.1 ± 1.3 (p< 0.05)
D’Ancona and Coll. 2000 USA	-409 patients undergoing off-pump CABG via median sternotomy. -1145 grafts tested with TTFM.	Retrospective cohort study (level 2b)	Clinical applicability of TTFM in detecting anastomotic failures, even as imperfections	-41/1145 grafts revised in 33 patients.	-Absence of control group with a gold standard of grafts verification -4 curves not included in the analisys due to technical problem. -no information about mid-term angiographical patency in the 3 conduits with altered flow with no technical problem at the revision
				34 (91.9%) were revised for both low flow and
				After revision, all flow patterns significantly improved: MGF from 3.85 ± 4.63 to 32.47 ± 28.59 ml/min with proximal snare (P< 0.0001) and from 6.58 ± 6.00 to 36.29 ± 26.91 ml/min without snare (P< 0.0001). PI from 38.45 ± 56.56 to 3.03 ± 1.6 with snare and from 24.44 ± 46.51 to 2.80 ± 1.68 without snare (P< 0.0001).
Takami and Coll. 2001 Japan	-82, including 37 internal thoracic arteries, were intraoperatively evaluated using TTFM. -Coronary angiograms were performed 14 ± 5 days after CABG.	Retrospective cohort study (level 2b)	To check the validity of intraoperative flow measurement in predicting CABG quality by comparison with postoperative quantitative angiography.	Significant differences in MGF, PI, %BF, and FFT ratio between patent and non-patent grafts: a)MGF: 51.2 ± 30.7 vs 13.7 6 13.8 mL/min, p=0.0004; b)PI: 2.74 ± 1.91 vs 21.8 ± 25.4, p=0.021 c) %BF: 2.82% ± 6.98% vs 28.3% ± 33.6%, p=0.027 d)FFT ratio: 3.20 ± 2.11 vs 0.65 ± 0.26, p=0.0003).	-No significant cut-off value to distinguish patent from nonpatent grafts in MGF, PI, or %BF because of small sample size and low event incidence (failing grafts).
				-not possible to define a precise cut-off value to distinguish patent from nonpatent grafts in MGF, PI, or %BF
				-Only FFT ratio appeared to have a cut-off value.All the non patent grafts yielded a FFT ratio less than 1.0
Kim and Coll. 2005 South Korea	-58 total arterial Off Pump CABG patients evaluated with intraoperative TTFM and postoperative angiography as patency control. -Flow pattern, MGF, PI, %BF, and FFT ratio were measured/calculated intraoperatively at TTFM.	Retrospective cohort study (level 2b)	-To assess the validity of intraoperative TTFM in predicting graft flow abnormalities measuring and comparing results between 103 normal and 14 abnormal (occluded or competitive) grafts.	-3 in situ right gastroepiploic artery grafts anastomosed to the right coronary territories were occluded at postop angiography. -Flow competitions were observed in 11 distal anastomoses (6/73 in the left coronary territories vs 5/44 in the right coronary territories, p>0.05),-None of the grafts showed anastomotic stenosis of greater than 50% of the grafted coronary artery. -3 grafts showed mild stenosis of less than 50% of the grafted coronary artery, and they were regarded as patent grafts	-Low sample size -Only performing diagnostic accuracy without multivariate and ROC analisys
			-3 major end-point : a) to present the normal flow pattern of grafts anastomosed to the right and left coronary territories;	a)When we compared the TTFM findings based on the feeding arteries, there were no significant differences between the groups of right gastroepiploic artery (n. 28) and ITA (n .8)
			b) to assess the validity of TTFM by comparing it with graft patency assessment from early postoperative angiography;	b) The abnormal grafts demonstrated significantly lower MGF and FFT ratio and higher PI and %BF than normal grafts (p < 0.05).
			c) to establish cutoff values for the TTFM variables for detecting graft flow impairment in OPCAB patients who received arterial grafts	c) using the criteria to predict abnormal grafts as systolic dominant flow curve, MGF less than 15 mL/min; PI > 3 in the left coronary territories, and > 5 in the right coronary territories; and %BF > 2% the sensitivity and specificity of TTFM to detect graft flow abnormality were 96.2% and 76.9%, respectively.
Di Giammarco and Coll. 2006 Italy	-3567 patients submitted to isolated myocardial revascularization. -157 (4.4%) underwent both intraoperative TTFM and angiography at follow-up (6.7 ± 4.8 months) -304 grafts, 227 arterial conduits, and 77 saphenous vein grafts were checked According to angiography at follow-up, grafts were classified as : • (group A) : completely functioning • (group B) : failed	Retrospective cohort study (level 2b)	-to evaluate the possibility to predict postoperative graft patency in coronary surgery by means of intraoperative TTFM	-(group A) : 266 grafts; -(group B) : 38 grafts	-Retrospective study
				MGF (OR, 0.86; P= .002), PI (OR, 1.3; P= .031), %BF (OR, 1.1; P= .041) confirmed to be predictive variables of graft failure
				ROC analsys overall gafts: MGF 0.89 0.85-0.93 <.001; PI 0.72 0.62-0.82 <.001 ; %BF 0.89 0.84-0.94 <.001.
				Cutoff and Sensitivity, Specificity and Positive Predictive Value (PPV) in overall grafts: MGF(ml/min) 15 0.87 0.87 0.95; PI 3 0.66 0.67 0.66; %BF 3 1 0.67 0.53
Tokuda and Coll. 2007 Japan	-123 patients who underwent both TTFM and early angiography between 2002 and 2006. -Postoperative angiography performed 16.2 ± 12.6 days after surgery. Univariate logistic regression used to obtain odds ratios for early grafts failure. Optimal cutoff values of MGF, PI, and %BF, to predict early graft failure, were determined by means of ROC curve analysis and AUC. -Sensitivity, specificity, PPV, and NPV also calculated.	Retrospective cohort study (level 2b)	-to predict early graft failure	(group A): 225/261 gratfs were normal and fully patent by angiography with following intraoperative TTFM findings: MGF (mL/min) 45.5 ± 28.9; PI 2.74 ± 2.27; %BF 1.98 ± 4.16.	-Data from 6 grafts lost in the analisys because of incorrect storage in flowmeter system. -Small number of occluded grafts (8 to the LCA and 6 to the RCA territory) -occluded graft category not considered as endpoint “per se” -ROC analysis not performed -too wide PPV range of each parameter (0.31 to 0.8).
			-to find optimal cutoff values for MGF, PI, and %BF	(group B): 36 grafts were failing (22 abnormal grafts and 14 occluded) with following intraoperative TTFM findings: In the 22 abnormal grafts MGF (mL/min) 29.6 ± 20.8; PI 4.21 ± 3.07; %BF 6.74 ± 10.2. In 14 occluded grafts, MGF (mL/min) 15.1 ± 21.0; PI 18.3 ± 28.9; %BF 21.1 ± 28.7.
			-to evaluate differences between grafts to the Left Coronary Arteries or grafts to the Right Coronary Arteries
Tokuda and Coll. 2008 Japan	Out of 142 patients submitted to intraoperative TTFM, 123 patients who had postoperative angiography were included in the study. In the early postoperative angiography group, 36 of 261 grafts (5.4%) were found to be occluded or stenotic. Subsequently, 51 patients underwent follow-up angiography between 1 and 4 years after surgery. Patients grouped in A (occluded grafts) and B (patent grafts)	Retrospective cohort study (level 2b)	To describe TTFM ability to predict midterm graft failure. Multivariate stepwise logistic regression analysis performed to identify independent risk factors.	Group A vs Group B ; MGF: 26.5 ± 14.7 versus 47.7 ± 30.2, (p < 0.01); % BF: 6.13 ± 9.47 versus 2.30 ± 5.02, (p<0.05).	-small sample size (21 events of new occlusion or stenosis) limited the ability of logistic regression analysis to detect risk factors -postoperative angiography not taken in all patients
				Transit time flow measurement variables: MGF (mL/min) 0.96 (0.93–0.98), p< 0.01; PI 1.14 (0.98–1.40), p= 0.12; %BF 1.08 (1.01–1.17), p< 0.05; Venous graft 2.08 (0.76–5.61), p= 0.15; Time to angiography (mo) 1.06 (1.01–1.13), p< 0.05.
				None of Patients variables founded as statistical predictors (p<0.05)
Becit and Coll. 2007 Turkey	Two series of 100 consecutive patients, Group A (control group, not submitted to intraoperative TTFM) and Group B (study group, submitted to intraoperative TTFM) are object of this study.	Retrospective cohort study (level 2b)	To evaluate the effect of detection of graft dysfunction by intraoperative TTFM on surgical results of on-pump CABG.	No significant differences in patient data between Group A or Group B	Not randomized study; Low sample size and low event incidence rate.
			Primary End-point: Overall mortality.	No significant differences in patient data between Group A or Group B
			Secondary End-point: Overall morbidity, Re-exploration for bleeding, Deep sternal infection, IABP insertion, Peri-or postoperative myocardial infarction.	Overall morbidity (n16) p <0.05; IABP insertion (n.7) p <0.05; Peri-or postoperative infarction (n.5) p <0.05; were significantly lower in Group B than Group A. No differences for Re-exploration for bleeding (n.3) p >0.05; Deep sternal infection (1) p >0.05.

Comment(s)

All well designed and appropriately sized studies were analyzed and compared. Based on a recent prospective intraoperative angiographic study reporting up to 13% of graft failure [3], clinical evidence concerning intraoperative TTFM in coronary surgery has been reported since mid-nineties. Canver and Coll.[4] first reported on clinical use of TTFM without any adverse event related to the method. Their experience showed abnormal flow parameters in 2 patients out of 63 in which flow impedance was caused by LIMA pedicle twisting. D’Ancona and Coll.[5] report a large series of TTFM checked grafts detecting 9.9% of failure. Out of 32 failing grafts revised, 6 (19%) were found to be completely obstructed; 9 (28%) showed a minimal stenosis; 12 (37%) had an intimal flap or a clot in the native coronary vessel; in 5 cases (16%) there was a kinked conduit or an artery dissection. Leong and Coll. [6] a series of 116 patients, 49 of whom operated without CPB. They suspected a graft malfunction in 7 conduits on the basis of TTFM. All grafts suspected to be failing came back to normal parameters after revision. D’Ancona and Coll. [7] retrospectively analysed 1145 grafts in 409 patients. Out of 37 suspected failing grafts, 34 were successfully submitted to revision. They first described 3 additional grafts (8.1%) in which, in front of a low MGF (<7 ml/min), no technical failure was found and no changes after revision were observed. In spite of the reported not perfect sensitivity for intraoperative technical failure, the Authors give no further information about mid-term angiographic patency of those 3 conduits. In the attempt to reach a better diagnostic accuracy and reproducibility as well, other Authors described the predictive power of the method assessing cutoff values of various parameters. Takami and Coll. [8] analysed 82 grafts submitted to intraoperative TTFM verification and angiographic control after 14±5 days postoperatively. They found a statistical difference between patent and not patent grafts concerning MGF, insufficiency ratio (%BF), PI and fast Fourier transformation (FFT) but evident cutoff were detected only for the latter. This was probably due to small sample size and low incidence of failing grafts in this experience. Kim and Coll.,[9] reported on 58 coronary patients submitted to intraoperative TTFM and immediate postoperative angiography (1,1±0,4 days) in which they detected 14 abnormal grafts out of 117 total. They set cutoff values of the main parameters of TTFM on the basis of some preliminary experience without performing any statistical evaluation. Di Giammarco and Coll. [10] reported on 304 grafts in 157 patients submitted to intraoperative TTFM and postoperative angiography at a mean follow-up of 6,7±4,8 months from the operation. They found at univariate analysis that peak flow, MGF, PI and %BF were independent predictors of graft failure observed in 38 grafts of the reported experience. They first applied ROC analysis to set cutoff values of TTFM parameters finding MGF <15 ml/min, PI >3, %BF >3% as the more accurate predictors for short term negative outcome. In addition they report that more than 50% of failing grafts in their experience had to be considered as functional occlusion with the feature of low MGF with, huge %BF and a very high PI. A similar statistical methodology was used by Tokuda and Coll. [11], setting optimal PI and %BF cutoff at 5 and 4.1 respectively. Some evidences have been published concerning the role of TTFM in predicting midterm graft failure and patients outcome. Tokuda and Coll. [12] report on mid-term analisys of patency. They considered 261 coronary grafts in 123 patients intraoperatively verified by TTFM and submitted to early postoperative angiography. They found 5,4% of grafts stenotic or occluded. They analysed within the group 104 grafts fully patent at 1-y. This analysis demonstrated that within a range from 1 to 4 years postoperatively MGF and %BF were independent predictors of failure at univariate analysis. Pulsatility index did not reach statistical significance. Intraoperative graft verification was also associated to patients outcome. Becit and Coll. [13], report on a consecutive series of 100 patients in which 3% of total grafts in 9% of patients were revised with a significant reduction of morbidity and mortality in TTFM compared to no-TTFM group.

Clinical Bottom Line

Transit-Time flow measurement with multiparametric analysis demonstrates its usefulness in detecting intraoperative graft failure, improving immediate CABG outcome and predicting graft fate at either early and mid-term interval after surgery. This can achieve a better clinical outcome with a low rate of late adverse events.

References

1. Dunning J, Prendergast B, Mackway-Jones K Towards evidence-based medicine in cardiothoracic surgery: best BETS Interact Cardiovasc Thorac Surg. 2003 Dec;2(4):405-9.
2. CEBM. Oxford Centre for Evidence Based Medicine Oxford Centre for Evidence Based Medicine 2003; accessed May 1, 2003
3. Zhao DX, Leacche M, Balaguer JM, Boudoulas KD, Damp JA, Greelish JP, Byrne JG. Routine intraoperative completion angiography after coronary artery bypass grafting and 1-stop hybrid revascularization J Am Coll Cardiol. 2009 Jan 20;53(3):232-41.
4. Canver CC, Dame NA Ultrasonic assessment of internal thoracic artery graft flow in the revascularized heart Ann Thorac Surg 1994;58:135–8
5. D'Ancona G, Karamanoukian HL, Salerno TA, Schmid S, Bergsland J. Flow measurement in coronary surgery. The Heart Surgery Forum 1999; 2 (2):121–124
6. Leong DK, Ashok V, Nishkantha A, Shan YH, Sim EK. Transit-Time flow measurement is essential in coronary artery bypass grafting Ann Thorac Surg 2005;79:854–8.
7. D'Ancona G, Karamanoukian HL, Ricci M, Schmid S, Bergsland J, Salerno TA. Graft revision after transit time flow measurement in off-pump coronary artery bypass grafting Eur J Cardiothorac Surg 2000;17:287-293.
8. Takami Y, Ina H. Relation of intraoperative flow measurement with postoperative quantitative angiographic assessment of coronary artery bypass grafting Ann Thorac Surg 2001;72:1270–4.
9. Kim KB, Kang CH, Lim C Prediction of graft flow impairment by intraoperative transit time flow measurement in off-pump coronary artery bypass using arterial grafts. Ann Thorac Surg 2005;80:594-598
10. Di Giammarco G, Pano M, Cirmeni S, Pelini P, Vitolla G, Di Mauro M. Predictive value of intraoperative transit-time flow measurement for short-term graft patency in coronary surgery. J Thorac Cardiovasc Surg 2006;132:468-74.
11. Tokuda Y, Song MH, Ueda Y, Usui A, Akita T. Predicting Early Coronary Artery Bypass Graft Failure by Intraoperative Transit Time Flow Measurement Ann Thorac Surg 2007;84:1928-1933
12. Tokuda Y, Song MH, Oshima H, Usui A, Ueda Y. Predicting midterm coronary Artery bypass graft failure by intraoperative transit time flow measurement. Ann Thorac Surg 2008;86:532-536.
13. Becit N, Erkut B, Ceviz M, Unlu Y, Colak A, Kocak The impact of intraoperative transit time flow measurement on the results of on-pump coronary surgery Eur J Cardiothorac Surg 2007;32:313-318.