Non-invasive measurement of intestinal tissue oxygen saturation for evaluation of reconstructed blood flow in rectal cancer surgery: HiSCO-09 study

Anastomotic leakage (AL) is one of the most serious complications of colorectal cancer (CRC) surgery1–3 and interruption to anastomotic blood flow is considered an important risk factor for its occurrence4,5. The effectiveness of blood flow evaluation using indocyanine green fluorescence angiography (ICG-FA) has been verified in several clinical trials6–10; however, this method of evaluation has limitations in terms of quantification and objectivity, and carries a risk of anaphylaxis. Considering these limitations, this study focused on the measurement of tissue oxygen saturation (rSO2) using INVOS™ (manufactured by Covidien), a device that employs near-infrared spectroscopy (NIRS) to quantitatively measure rSO2. NIRS-based rSO2 measurements have been widely used to monitor cerebral blood flow during cardiovascular surgery. The hypothesis of this study therefore was that rSO2 measurements using NIRS could be used to evaluate anastomotic blood flow in the bowel11,12. To mitigate the risk of AL in left-sided colorectal surgery, preservation of the left colic artery (LCA) is frequently performed to maintain blood flow. In theory, preservation of the LCA may enhance blood flow to the site of the planned reconstruction. The aim of this multicentre prospective study was to examine the utility of rSO2 measurement using INVOS™ for assessing anastomotic intestinal blood flow, with or without preservation of the LCA, and to evaluate whether this correlates with AL. A multicentre prospective observational study was conducted at seven centres of the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). The inclusion criteria were patients: with left-sided CRC who underwent reconstruction using the double stapling technique with an automated suture device; with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; with ASA physical status I or II; and aged between 20 and 80 years at the time of consent. The exclusion criteria were patients: who were scheduled to undergo more than one anastomosis; who were scheduled to undergo simultaneous resection of other organs due to multiple cancers; who were suffering with intra-abdominal infection (peritonitis or abscess); and who were deemed ineligible by the physician in charge. Consistent with the guidelines of the Declaration of Helsinki (Fortaleza, Brazil, October 2013), this study was approved by the Institutional Review Board and registered with the Japanese Clinical Trials Registry (UMIN-CTR000038179). Written informed consent was obtained from all the patients for the use of their clinical data. Non-invasive tissue oxygenation was measured using an INVOS™ 5100C oximeter (Medtronic, Jacksonville, USA). This monitor uses a light-emitting diode that generates near-infrared light at two wavelengths (730 and 810 nm) and two silicon photodiodes that act as light detectors. These data are interpreted as a single numerical value expressed as rSO2. The rSO2 values were measured at three locations both before and after division of the mesentery: the planned anastomosis site (points B and E); 10 cm on the oral side of the anastomosis (points A and D); and 10 cm on the anal side of the anastomosis (points C and F) (Fig. 1a). Measurements were taken by the operating surgeon, with no intervention or change to the operative strategy based on these measurements. Details of the surgical technique and methodology for acquiring the rSO2 measurements are presented in the Supplementary Methods. The primary endpoint was to explore variations in rSO2 values, with or without LCA preservation. The secondary endpoint was to correlate rSO2 with AL. Location of measurement for rSO2 (a) and Box plots of the rSO2 values of each site (b) Between October 2019 and September 2021, 302 patients were enrolled of which 291 were included in the analysis. A total of 11 patients were excluded because of an inability to perform a double stapled anastomosis (6 patients), measurement failure (2 patients), poor performance status (1 patient), multiple cancers (1 patient), or sensor failure (1 patient). Patient characteristics and surgical outcomes are shown in Table S1. LCA preservation was performed in 94 (32.3 per cent) patients and postoperative AL occurred in 25 (8.6 per cent) patients. The rSO2 measurements are shown in Fig. 1b. Both before and after mesenteric resection, rSO2 was significantly higher from the anal side to the oral side. Notably, the rSO2 at point D (beyond the division of the vessel and after division of the mesentery) was clearly lower than that at all other points, suggesting that rSO2 reflects arterial blood flow. Propensity score matching was used to allow independent assessment of changes in rSO2 associated with LCA preservation (Table S2). In an analysis of 178 patients adjusted for patient factors, rSO2 was significantly higher with LCA preservation—at all measurement sites (Table S3). The rSO2 value at the anastomotic site after division of the mesentery (point E) was lower in the AL group compared with the No-AL group (69 versus 77 per cent; P = 0.038); a receiver operating characteristic (ROC) curve was generated to determine a cut-off value of 74 per cent. Results of the univariable and multivariable analyses of AL are presented in Table 1, demonstrating that an rSO2 value of less than or equal to 74 per cent at the anastomotic site after division of the mesentery (point E) was an independent predictor of AL (OR 3.35 (95 per cent c.i. 1.13 to 9.94); P = 0.029). Risk factors for anastomotic leakage in univariable and multivariable analysis ECOG, Eastern Cooperative Oncology Group; rSO2 (point E), tissue oxygen saturation measured at the planned anastomosis site after mesenteric resection. Risk factors for anastomotic leakage in univariable and multivariable analysis ECOG, Eastern Cooperative Oncology Group; rSO2 (point E), tissue oxygen saturation measured at the planned anastomosis site after mesenteric resection. The need for precision surgery has led to the widespread use of intraoperative perfusion assessment using ICG-FA in gastrointestinal surgery. Jafari et al.6 reported the utility of ICG-FA in preventing AL; however, a subsequent multicentre phase III RCT found that ICG-FA failed to decrease the occurrence of AL, although it permitted the visualization of intestinal blood flow7. They7 acknowledged that the early termination of the case series and the inability to quantitatively measure ICG-FA made it a subjective assessment of perfusion by the surgeon. Several studies have assessed intestinal perfusion using rSO2 and new devices are also being evaluated for practical applications13,14. In this study, the focus was on a quantifiable measure of rSO2 using INVOS™. The findings revealed that rSO2 was notably lower in areas distant from the nutrient vessels, that is regions of increased ischaemia, both before and after division of the mesentery. These results suggest that rSO2 may be a valid means of quantitatively and objectively assessing intestinal blood flow. As the rSO2 value increases towards the oral side of the intestine, setting the anastomotic line with reference to the rSO2 value may prevent postoperative AL. In addition, the fact that rSO2 at the planned anastomotic site was an independent risk factor for AL is a novel finding. This study focused on the changes in rSO2 with and without LCA preservation. Although LCA preservation may be beneficial in terms of blood flow, previous reports have yielded mixed results on the prevention of AL15–18. In the present study, higher rSO2 readings were obtained with LCA preservation, suggesting that this may be a viable means of maintaining good intestinal blood flow. This study’s main limitation is that, whilst it is a multicentre prospective study, it is not an RCT and, due to the potential for confounders, cannot directly evaluate the effectiveness of rSO2 quantification with INVOS™ for prevention of AL. In conclusion, the use of INVOS™ to measure rSO2 may serve as a non-invasive, quantitative method of evaluating intestinal perfusion and may therefore have a role in reducing the incidence of AL. Furthermore, preservation of the LCA may be significant in maintaining intestinal blood flow and further investigation is warranted to determine its role in the prevention of AL. The authors have no funding to declare. The authors thank all of the surgeons and patients who participated in this trial. The authors would also like to thank Editage for editing and reviewing this manuscript with regard to English language. Hisaaki Yoshinaka (Data curation, Visualization, Writing—original draft), Manabu Shimomura (Investigation, Resources, Supervision, Writing—original draft, Writing—review & editing), Hiroyuki Egi (Conceptualization, Methodology), Wataru Shimizu (Investigation, Resources), Tomohiro Adachi (Investigation, Resources), Satoshi Ikeda (Investigation, Resources), Masahiro Nakahara (Investigation, Resources), Yasufumi Saitoh (Investigation, Resources), Kazuhiro Toyota (Investigation, Resources), Masanori Yoshimitsu (Investigation, Resources), Shintaro Akabane (Investigation, Resources), Takuya Yano (Investigation, Resources), Minoru Hattori (Visualization), and Hideki Ohdan (Conceptualization, Project administration, Supervision). The authors declare no conflict of interest. Supplementary material is available at BJS online. The data that support the findings of this study are not openly available (due to reasons of sensitivity, for example human data) and are available from the corresponding author upon reasonable request.