Anterior Resection for Rectal Cancer and Visceral

692SJS0010.1177/1457496915593692Visceral blood flow after anterior resectionm. Rutegård, et al. Original Article Anterior Resection for Rectal Cancer and Visceral Blood Flow: An Explorative Study M. Rutegård 1, N. Hassmén 1, O. Hemmingsson 1, M. M. Haapamäki 1, P. Matthiessen 2, J. Rutegård 1 1 Department of Surgical and Perioperative Sciences, Umeå University Hospital, Umeå University, Umeå, Sweden 2 Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden Abstract Background and aims: Impaired blood perfusion may be implicated in anastomotic leakage after anterior resection for rectal cancer. We investigated whether high ligation of the inferior mesenteric artery or total mesorectal excision compromises visceral blood flow in the colonic limb and the rectal stump, respectively. Material and methods: A prospective cohort study was conducted in a university hospital setting. We used Laser Doppler flowmetry to evaluate the impact of level of tie on colonic limb perfusion and the extent of the mesorectal excision on the rectal blood flow. In the rectum, different quadrants were also assessed. The Mann Whitney U test was used to compare mean blood flow s between groups. Results: Some 23 patients were recruited in a convenience sample during a period in 2012 2013. The mean blood flow was not decreased after high tie compared to low tie surgery (1.71 vs 1.19; p = 0.28). Total mesorectal excision reduced the mean blood flow in the rectum, as compared with partial mesorectal excision (0.76 vs 1.28; p = 0.14). This was especially pronounced in the posterior aspect of the rectum (0.66 vs 1.68; p = 0.02). Conclusion: High tie ligation did not seem to decrease colonic limb perfusion, while total mesorectal excision may decrease rectal blood flow. The posterior quadrant of the rectum might be particularly vulnerable to the dissection involved in total mesorectal excision. Key words: Inferior mesenteric artery; left colic artery; mesorectal excision; high tie; Laser Doppler flowmetry Correspondence: Martin Rutegård Department of Surgical and Perioperative Sciences Umeå University Umeå University Hospital SE-901 85 Umeå Sweden Email: martin.rutegard@surgery.umu.se Scandinavian Journal of Surgery 2016, Vol. 105(2) 78 83 The Finnish Surgical Society 2015 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/1457496915593692 sjs.sagepub.com

Visceral blood flow after anterior resection 79 Introduction Anterior resection is considered a standard procedure for patients with cancer in the mid and high rectum. With the advent of the total mesorectal excision (TME) technique, complications such as anastomotic leakage have been increasing in frequency (1, 2). Some risk factors for anastomotic leakage, such as advanced comorbidity (3), male sex (4 6), and tumor height (4), are unavoidable. Others are a consequence of oncological nale, such as preoperative radiotherapy (3, 6). Surgically related factors also play a role, where the use of a diverting stoma has been shown to reduce symptomatic leaks (5, 7), while intraoperative surgical complications (8) and blood loss (3 5) increase the risk of an anastomotic breakdown. There is still considerable controversy as to whether the use of high ligation of the inferior mesenteric artery predisposes the patient to anastomotic leakage as a consequence of compromised perfusion (9 12). Attempts have been made to quantify the effect of high tie ligation on the perfusion of the colonic limb of the anastomosis, where it seems that the use of a high tie consistently reduces blood flow (13, 14), as measured by laser Doppler flowmetry. Moreover, the same method has been employed to suggest that the circulation of the rectal stump might be more predictive of anastomotic leakage than the proximal limb perfusion (15); these data are supported by the anatomical observation that the collateral blood flow is particularly sparse in the distal rectum (16), possibly making this region a watershed area and vulnerable to extensive dissection, such as in TME surgery. When oncologically feasible, partial mesorectal excision (PME) is an alternative for tumors in the upper rectum; this technique has not been implicated as strongly in leakage (5). In addition to the above, clinical experience and some data indicate that most anastomotic leaks are located in the posterior aspect of the rectum (17), which has not hitherto been characterized in relation to blood flow. Therefore, we designed an explorative study, aiming at describing (1) the effects of high tie on the colonic microcirculation, (2) the impact of TME surgery on the rectal microcirculation, and (3) the microcirculation in different rectal quadrants. Material and Methods Study Design This is a prospective, single-center study conducted at Umeå University Hospital, Sweden, during the period February 2012 to September 2013. After signing informed consent, patients with verified rectal cancer or high-grade dysplasia were included in a convenience sample. All patients were subjected to anterior resection in a colorectal unit within an established enhanced recovery after surgery program. Thoracic epidural analgesia was used and surgery was performed using a midline abdominal incision. The use of a high or low tie was at the surgeon s discretion, and the splenic flexure was mobilized selectively. TME was performed for tumors located in the mid and lower rectum, while PME was used for higher tumors only. Diverting stomas were used routinely in TME patients, while only selectively performed for PME patients. Complications were registered up to 30 days after surgery. We measured blood flow with Laser Doppler flowmetry (Moor Instruments Ltd, Millwey, Axminster, UK), the principles of which have been described elsewhere (18). The instrument produces light with a wavelength of 780 nm, interacting with moving blood cells in the tissue, inducing a Doppler shift. The backscattered light is detected by a photocell in a probe, which collects measurements to a depth of 1 mm. The magnitude of the Doppler shift correlates to the product of the number and mean velocity of the moving cells in the illuminated tissue volume. This is also known as flux and is expressed in perfusion units (PU). The software eliminates motion artifacts and calculates mean values during intervals of 0.1 s. Measurements were conducted for at least 20 s each, initiated only after stable recordings were produced, and the mean value was calculated for the measurement period. We conducted both intraluminal and serosal measurements. Preoperatively, after induction of anesthesia, we performed intraluminal measurements of the rectum, facilitated by an anoscope. At the level of the dentate line, we registered measurements in four quadrants: anterior, posterior, left, and right. Intraoperatively, a first serosal measurement was conducted immediately after laparotomy at the antimesenteric side of the colon 2 cm proximal to the location of the division of the descending or sigmoid colon. A second measurement was performed after division of the inferior mesenteric artery (high tie) or the superior rectal artery (low tie), beside the transverse staple line and also 2 cm proximally, where the anvil for the circular stapler was to be inserted for the creation of a side-to-end anastomosis. Postoperatively, the intraluminal measurements of the rectum were repeated at the same location, distal to the anastomosis. The anesthetist was instructed to withhold vasoactive drugs during measurements and inform the operator whether blood pressures were unstable, in case measurements were postponed until stabilization. Furthermore, mean arterial pressures were registered during measurements. The Regional Ethical Review Board in Umeå, Sweden, approved the study. Statistical Analysis For each patient, the colonic blood flow was calculated by dividing the mean of the measurements at the stapler line and the anastomotic site by the measurement at the colon; the rectal blood flow was derived by dividing the mean of the postoperative quadrant measurements by the mean of the preoperative quadrant measurements; the rectal quadrant blood flow s were calculated in a corresponding fashion. The mean s were compared with the non-parametric Mann Whitney U test. To assess whether mean arterial pressures differed between exposure groups, the means in patients with high and low tie as well as TME and PME were also compared. All p values were twotailed and considered statistically significant when

80 M. Rutegård, et al. below 0.05. The statistical software STATA 12.1 was used to perform all analyses. Results Patients A total of 35 patients were recruited into the study. Of these, 1 patient was excluded due to an intraoperative decision to perform abdominoperineal excision and 11 patients were excluded due to incomplete blood flow measurements. Some 23 patients remained in the final analysis. There were 22 R0 and 1 R1 resections. All diverting stomas were loop ileostomies, except for one transverse colostomy. All patients had either a side-toend or an end-to-end stapled anastomosis. Rectal washout was performed routinely. A total of 5 patients were operated with high tie ligation, while 18 patients had a low tie. Furthermore, 5 patients were subjected to PME and 18 patients had a TME. Clinical data are presented in Tables 1 and 2. No postoperative mortality was noted. Four patients sustained a symptomatic anastomotic dehiscence. All four leaks were detected by endoscopy or radiology following a clinical suspicion. They were all localized in the posterior quadrant of the rectum. Measurements Measurements before and after vascular ligation of the colonic perfusion indicated an increase in blood flow, regardless of ligation type. The largest increase was found in the high tie group, but the difference between the tie levels was not statistically significant (Table 3). Regarding the rectal microcirculation, TME surgery seemed to reduce blood flow compared to PME surgery, although this difference did not reach statistical significance (0.76 vs 1.28; p = 0.14). We stratified for the different rectal quadrants and found that blood flow was particularly reduced in the posterior aspect of the rectum after TME surgery compared to PME (0.66 vs 1.68; p = 0.02; Table 4). arterial pressures did not differ between high and low tie patients (72.8 vs 73.8; p = 0.85) or between TME and PME patients (75.6 vs 77.6; p = 0.55). Exploratively, we also investigated whether the four patients with an anastomotic leak, who all underwent TME surgery, had a particularly reduced blood flow in the posterior quadrant; there was no such apparent relationship (data not shown). Discussion This explorative study suggests that colonic perfusion is not markedly affected by the use of a high tie of the inferior mesenteric artery, while rectal microcirculation may be affected by TME surgery, particularly in the posterior quadrant. This is a small, hypothesis-generating study, conducted in a university hospital setting. All data were gathered prospectively, but we were unable to ensure a true consecutive sample, thus possibly introducing selection bias. The study size is admittedly a disadvantage, rendering multivariate analysis impossible and the Table 1 Demographic and clinical data by level of tie in 23 patients operated with anterior resection. Categorical variables High tie (n = 5) Low tie (n = 18) N (%) N (%) Sex Male 4 (80) 12 (66.7) Female 1 (20) 6 (33.3) ASA I 0 (0) 6 (33.3) II 4 (80) 9 (50) III 1 (20) 3 (16.7) Tumor stage Adenoma 2 (40) 1 (5.6) I 1 (20) 8 (44.4) II 2 (40) 2 (11.1) III 0 (0) 7 (38.9) Preoperative radiotherapy No 3 (60) 10 (55.6) Yes 2 (40) 8 (44.4) Resection type TME 3 (60) 15 (83.3) PME 2 (40) 3 (16.7) Type of anastomosis Side-to-end 2 (40) 13 (72.2) End-to-end 3 (60) 5 (27.8) Diverting stoma No 1 (20) 3 (16.7) Yes 4 (80) 15 (83.3) Symptomatic leakage No 4 (80) 15 (83.3) Yes 1 (20) 3 (16.7) Continuous variables (SD) (SD) Age (years) 67.8 (3.3) 65.3 (9) BMI (kg/m 2 ) 27.3 (4.2) 26.5 (3.7) Anastomotic height (cm) 5.5 (2.2) 4.9 (1.5) Perioperative bleed (ml) 870 (823) 763 (875) N: number; TME: total mesorectal excision; PME: partial mesorectal excision; SD: standard deviation; BMI: body mass index ; ASA: American Society of Anesthesiologists classification. threat of type II error a real issue. Nevertheless, patients served as their own control, reducing the threat of confounding. Similar studies on high tie ligation have been performed previously. A Japanese group performed laser Doppler flowmetry on patients operated for cancer of the rectum and the sigmoid colon; colonic measurements were made before and after clamping and showed marked reductions in perfusion after clamping, particularly for high tie patients (14). Those data are in contrast to this study s findings, but were also collected immediately after clamping, not permitting time for possible recruitment of collaterals and redistribution of regional blood flow and thus not quite mirroring the clinical situation when fashioning the anastomosis. A Dutch group using similar methodology, but comparing measurements immediately after

Visceral blood flow after anterior resection 81 Table 2 Demographic and clinical data by level of resection in 23 patients operated with anterior resection. Categorical variables TME (n = 18) PME (n = 5) N (%) N (%) Sex Male 14 (77.8) 2 (40) Female 4 (22.2) 3 (60) ASA I 6 (33.3) 0 (0) II 10 (55.6) 3 (60) III 2 (11.1) 2 (40) Tumor stage Adenoma 3 (16.7) 0 (0) I 7 (38.9) 2 (40) II 3 (16.7) 1 (20) III 5 (27.8) 2 (40) Preoperative radiotherapy No 10 (55.6) 3 (60) Yes 8 (44.4) 2 (40) Level of tie High tie 3 (16.7) 2 (40) Low tie 15 (83.3) 3 (60) Type of anastomosis Side-to-end 15 (83.3) 0 (0) End-to-end 3 (16.7) 5 (100) Diverting stoma No 0 (0) 4 (80) Yes 18 (100) 1 (20) Symptomatic leakage No 14 (77.8) 5 (100) Yes 4 (22.2) 0 (0) Continuous variables (SD) (SD) Age (years) 65.4 (8.9) 67.4 (4.7) BMI (kg/m 2 ) 26.7 (3.8) 26.8 (3.6) Anastomotic height (cm) 4.3 (0.9) 7.7 (0.8) Perioperative bleed (ml) 895 (916) 390 (347) N: number; TME: total mesorectal excision; PME: partial mesorectal excision; SD: standard deviation; BMI: body mass index ; ASA: American Society of Anesthesiologists classification. laparotomy to measurements before fashioning the anastomosis, found that there were blood flow reductions in high tie patients; however, low tie patients displayed an increase in blood flow, a difference between groups that was statistically significant (13). An Italian group considered both the proximal and distal circulations in surgery for rectosigmoid cancers, where TME surgery was performed for cancers in the middle and lower rectum. Low tie was routinely performed, and measurements were made at the colonic serosa and at the rectal mucosa, after division of the artery and before fashioning the anastomosis. The authors noted that most patients displayed colonic as well as rectal blood flow reductions, but the latter were more predictive of anastomotic leaks (15). No comparisons were made between PME and TME surgery, but the rectal microcirculation was markedly affected in the Table 3 Blood flow data (perfusion units) by level of tie. Location High tie Low tie Test for difference flow (PU) flow (PU) Colon 158.7 1.71 45.5 1.19 0.28 Stapler line 117.8 39.6 Anastomotic site 150.4 50.7 P value* PU: perfusion unit. Ratios denote the mean of the stapler line and the anastomotic site measurements divided by the colon measurements. Colon: before vascular ligation, 2 cm proximal to the anastomosis; stapler line: after vascular ligation, beside the stapler line; anastomotic site: after vascular ligation, 2 cm proximal to the stapler line. * Mann Whitney U test. above study, in accordance with the TME subset in the present data. Contrary to previous research and perhaps also to surgical intuition, we could not find a reduction in colonic blood flow with high tie ligation; in fact, the point estimate suggested an increase in the blood flow. This may be due to chance as this is a small study, but one might also speculate that reactive hyperemia due to reperfusion injury plays a role. Moreover, experienced colorectal surgeons may also take into considen the possible perfusion compromise in the absence of sufficient collateral circulation when performing high tie surgery, thus transecting the colon more orally compared to low tie surgery this might explain that blood flow measured at the time of the fashioning of the anastomosis still does not vary much between level of tie. However, this relative shortening of the colonic limb in high compared to low tie surgery may lead to inadvertent traction on the anastomosis. Still, this risk should be small, since high tie of the artery combined with high tie of the inferior mesenteric vein allows for extensive mobilization of the splenic flexure. More expectedly, TME surgery seems to decrease rectal blood flow, although the difference from PME surgery did not reach formal statistical significance in the entire rectum. The possible blood flow reduction would be in accordance with previous angiographic findings that suggest that the lower rectum has a sparse network of intramural collaterals, in contrast to the more vascularized upper and mid rectum (16); this would implicate that the rectal microcirculation would be less sensitive to PME surgery. To our knowledge, blood flow has not previously been characterized in the different quadrants of the rectum, but the current finding that the posterior aspect in particular seems to be vulnerable to TME surgery may suggest a link to anastomotic leakage (17); however, we could not show such a connection in our data that is a research question which would need larger studies to investigate properly. In conclusion, we were unable to show a reduction in colonic blood flow with the use of high tie ligation in this series of patients operated with anterior resection. However, TME surgery might reduce rectal stump

82 M. Rutegård, et al. Table 4 Blood flow data by level of resection and stratified by rectal quadrant. Site Total mesorectal excision Partial mesorectal excision Test for difference flow (PU) flow (PU) p value* Rectum Rectum preop 359.0 0.76 342.1 1.28 0.14 Rectum postop 272.2 378.0 Quadrant Anterior preop 111.0 0.90 146.6 0.99 0.55 Anterior postop 82.6 125.3 Right preop 101.9 0.82 100.2 1.43 0.14 Right postop 87.5 120.7 Posterior preop 126.9 0.66 88.6 1.68 0.02 Posterior postop 80.9 118.0 Left preop 95.6 0.99 81.9 2.26 0.23 Left postop 86.8 104.6 PU: perfusion unit. Ratios denote postoperative rectal measurements divided by preoperative measurements. * Mann Whitney U test. blood flow in comparison with PME surgery, and the posterior quadrant of the rectum may be particularly vulnerable. It is still unclear whether this may contribute to anastomotic leakage, and more detailed and larger studies are needed to advance this field. Acknowledgements None. Declan of Conflicting Interests The authors declare that there is no conflict of interest. Ethical Approval Granted by the regional ethical review board at Umeå University. Funding This work was funded by the Cancer Research Foundation in Northern Sweden, The Swedish Society of Medicine, Dagmar Erb s Memorial Fund, and Research Council Västernorrland County. Informed Consent Informed consent was collected from all study participants. References 1. Carlsen E, Schlichting E, Guldvog I et al: Effect of the introduction of total mesorectal excision for the treatment of rectal cancer. Br J Surg 1998;85(4):526 529. 2. Eriksen MT, Wibe A, Norstein J et al: Anastomotic leakage following routine mesorectal excision for rectal cancer in a national cohort of patients. Colorectal Dis 2005;7(1):51 57. 3. Jestin P, Pahlman L, Gunnarsson U: Risk factors for anastomotic leakage after rectal cancer surgery: A case-control study. Colorectal Dis 2008;10(7):715 721. 4. Bertelsen CA, Andreasen AH, Jørgensen T et al: Anastomotic leakage after anterior resection for rectal cancer: Risk factors. Colorectal Dis 2010;12(1):37 43. 5. Law WL, Chu KW: Anterior resection for rectal cancer with mesorectal excision: A prospective evaluation of 622 patients. Ann Surg 2004;240(2):260 268. 6. Matthiessen P, Hallbook O, Andersson M et al: Risk factors for anastomotic leakage after anterior resection of the rectum. Colorectal Dis 2004;6(6):462 469. 7. Matthiessen P, Hallbook O, Rutegård J et al: Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: A randomized multicenter trial. Ann Surg 2007;246(2):207 214. 8. Matthiessen P, Hallbook O, Rutegård J et al: Intraoperative adverse events and outcome after anterior resection of the rectum. Br J Surg 2004;91:1608 1612. 9. Rutegård M, Hemmingsson O, Matthiessen P et al: High tie in anterior resection for rectal cancer confers no increased risk of anastomotic leakage. Br J Surg 2012;99(1):127 132. 10. Hinoi T, Okajima M, Shimomura M et al: Effect of left colonic artery preservation on anastomotic leakage in laparoscopic anterior resection for middle and low rectal cancer. World J Surg 2013;37(12):2935 2943. 11. Trencheva K, Morrissey KP, Wells M et al: Identifying important predictors for anastomotic leak after colon and rectal resection: Prospective study on 616 patients. Ann Surg 2013;257(1):108 113. 12. Bostrom P, Haapamaki MM, Matthiessen P et al: High arterial ligation and risk of anastomotic leakage in anterior resection for rectal cancer in patients with increased cardiovascular risk. Colorectal Dis. Epub ahead of print 8 April 2015. DOI: 10.1111/ codi.12971. 13. Komen N, Slieker J, De Kort P et al: High tie versus low tie in rectal surgery: Comparison of anastomotic perfusion. Int J Colorectal Dis 2011;26(8):1075 1078. 14. Seike K, Koda K, Saito N et al: Laser Doppler assessment of the influence of division at the root of the inferior mesenteric artery on anastomotic blood flow in rectosigmoid cancer surgery. Int J Colorectal Dis 2007;22(6):689 697.

Visceral blood flow after anterior resection 83 15. Vignali A, Gianotti L, Braga M et al: Altered microperfusion at the rectal stump is predictive for rectal anastomotic leak. Dis Colon Rectum 2000;43(1):76 82. 16. Allison AS, Bloor C, Faux W et al: The angiographic anatomy of the small arteries and their collaterals in colorectal resections: Some insights into anastomotic perfusion. Ann Surg 2010;251(6):1092 1097. 17. Floodeen H, Hallbook O, Rutegård J et al: Early and late symptomatic anastomotic leakage following low anterior resection of the rectum for cancer: Are they different entities? Colorectal Dis 2013;15(3):334 340. 18. Krohg-Sorensen K, Lunde OC: Perfusion of the human distal colon and rectum evaluated with endoscopic laser Doppler flowmetry. Methodologic aspects. Scand J Gastroenterol 1993;28(2):104 108. Received: January 9, 2015 Accepted: June 5, 2015