In recent years we have witnessed important surgical technological advancements (advanced energy devices, electrical staplers with gradual compression and triple row of stitches, increasingly refined laparoscopic instruments, robotic surgery, high resolution imaging systems associated or not with 3D), but nevertheless the biggest and most dramatic problem of colorectal surgery and consequently also the greatest cause of concern for the
surgeon continues to be the packaging and consequently the tightness of the intestinal anastomosis, considering that the percentage of post-operative leakage have remained practically unchanged [21]. In fact, the AL rate varies from 1–19% depending on the cases and anatomical location: ileocolic (1% - 8%); colocolic (2% - 3%); ileorectal (3% -7%); colorectal or coloanal (5% -19%) anastomosis [22–24]. Several factors have been associated with an increased risk of AL: male gender, age, comorbidity, increased ASA score, malnutrition, obesity, cigarette smoking, immunosuppression and in particular cortisone therapy, alcohol abuse, neoadjuvant radio-chemotherapy, advanced staged tumors, diverticulitis, low rectal anastomosis, prolonged operating times, blood loss or perioperative transfusions and intraoperative sepsis conditions [22, 25, 26]. Above all, an adequate vascular perfusion of the anastomosis is essential for optimal healing and for the prevention of AL [15, 27, 28]. As a result, intraoperative evaluation of intestinal ischemia could significantly reduce its risk during surgery. In the evaluation of intraoperative intestinal perfusion, the use of fluorescence of ICG, a dye already used for other applicationssince the 1960’s, seems to be a method that can potentially reduce the incidence of AL after colorectal surgery. Fluorescence Guided Surgery using ICG, allows the surgeon to view intestinal microperfusion in real time, is a fast and easy method to implement at the operating table, which can change the surgical resection strategy, as demonstrated by numerous recent studies [29–35].
In this retrospective study, the AL rate using guided NIR-ICG imaging is lower (3.6%) than the rate reported in the literature without using this method. If we also consider the case of remote stenosis of the colorectal anastomosis, which required endoscopic dilatative
treatment, our results show a relatively low and satisfactory level of complications (7.1%). We report the same percentage (7.1%) for changing surgical strategy (revision of strategy) due to insufficient perfusion as identified by fluorescence of the proximal intestinal stump which required further resection before the anastomosis. It is very likely that this is the key point of the effectiveness for ICG-based fluorescence, namely a better evaluation of perfusion compared to traditional macroscopic parameters (arterial pulse, bleeding, bowel color, peristalsis, etc.) [36].
Several studies have been published regarding the shifting of the resection line of the intestinal stump [21, 29, 32, 34, 35, 37–41]. Wada et al. reported that margin resection was changed in 16% of cases [32], while Jafari et al. reported in their Pillar II trial a rate of 6.5% of modification of margin resection [38]. Jun Watanabe et al. [39] in their guided ICG rectal resections, brought the section line more proximally towards a more adequate area of fluorescence in 12 cases (5.7%). Otero-Pineiro et al., during a comparative study on TaTME, reported a variation rate of the
proximal resection strategy of 28.7% with an incidence of AL of 2.5% as opposed to 11.3% of the non-ICG group [40]. Morales-Conde et al. [41], in a prospective study, hypothesized how the ICG could have a different utility depending on the type of surgery. They analyzed four group of patients: Group A, right hemicolectomy; Group B, segmental resection of the splenic flexure; Group C, left hemicolectomy; and Group D, anterior rectal resection. Fluorescence with ICG led to significant changes in the section line major in left hemicolectomy, followed by rectal resection and confirmed promise in reducing the AL rate, considering that it occurred in 5 patients (2.6%): 2 in group A (3%), 1 in C (1.2%), and 2 in D (5.7%).
Systematic reviews and meta-analysis also confirm that intraoperative use of fluorescence with ICG is a promising tool for reducing the risk of AL in colorectal surgery. However, the bias inherent in the fact that these are not RCT studies must be taken into consideration when interpreting these data sets. R. Blanco-Colino et al. [33] analyzed five articles on left colon surgery and report how the planned level of anastomosis was changed in 7.4% of cases (41 of 555 patients in the ICG-FI group), while showing an overall AL rate of 5.4%.
The meta-analysis by Renhui Shen et al. [42] reached the same result, even if conducted only on four non homogeneous non randomized studies. It is evident that the considerable heterogeneity and bias related to the mix of the cases operated in this study make difficult an accurate interpretation of the data. As a matter of fact, there are several studies that consider and compare different colorectal interventions. Impellizzeri G. et al. [43] analyzed left hemicolectomy, sigmoidectomy and rectal resection interventions, showing a change of strategy in 8.2% of cases with an AL rate of 3%. F. Ris et al. [37] in a multicenter phase II trial included benign and malignant pathologies operated with different colorectal procedures (right and left hemicolectomy, ileoanal and ileorectal pouches, rectal resections, Hartmann reversal) and they reported a revision rate of 5.8% with an incidence of AL of 2.4%.
In literature there are also two noteworthy multicenter RCTs (randomized controlled trials), one by De Nardi et al. [44], which evaluated 240 patients operated for left hemicolectomy and rectal resection, divided into two groups with and without ICG. They reported a revision rate of 11%, an AL rate of 5% (for the ICG group) vs 9% without ICG, but statistically not significant. Another key multicenter RCT which is still actively in progress, is the IntAct trial - [45] an ICG study of rectal surgery, which has the 90-day AL rate as its primary endpoint.
The evaluation of the ICG perfusion can be performed according to several steps: before and after the vascular preparation of the proximal intestinal stump, highlighting the fluorescence of the serous side; after the section of the stump on both sides, serous and mucous, and after the packaging of the anastomosis on the serous side.
In case of a "low" rectal resection (i.e. the distal part of the anorectal canal), the evaluation with ICG of the perfusion of the distal stump is always very difficult to visualize for anatomical reasons on the serous side and is almost exclusively entrusted to the evaluation of the mucous side by endoluminal view [46]. According to a recent experimental study, conducted by the group at the IHU Institute in Strasbourg [18], the perfusion of an ischemic segment of the pig colon was analyzed by fluorescence with ICG on the two sides, serous and mucous, and simultaneously the lactate concentration was measured in different areas. The study showed that the average ischemic zone of the mucous side, measured in mm, is significantly wider than the serous one. From this, it can be seen that an evaluation of intestinal perfusion only on the serous side can underestimate the extent of the ischemia area. Knowing this, in our study we also
evaluated the mucous side with ICG during the preparation of the proximal stump before the introduction of the stapler and, for the rectum, the evaluation of the same layer by endoanal evaluation after the packaging of the anastomosis. In our study, we evaluated eight out of 28 patients (one RAR and five laparoscopic hemicolectomies, one laparoscopic right hemicolectomy and one open right hemicolectomy, four in emergency and four in elective surgery) and none of them experienced AL or other post-operative complications. Further studies will be required to predict the optimal resection margin and the anastomosis site.
Morever we believe that the use of fluorescence in surgery is justifiable in relation to costs, considering the significantly potential patient benefits. In fact, AL not only increas the risk of mortality and LOS [36], but it has been associated with a long-term reduction in tumor-specific survival [47, 48].
A similar discourse could be made in case of emergency surgery. Indeed, with this bowel perfusion assessment, it could be possible to reduce the number of intestinal derivative operations in favor of intestinal resections with primary anastomosis. As the most recent
data suggests [22] a net saving in costs is related to lower patient morbidity, reduced hospitalization and a reduced number of intestinal reconstructions. It is clear that the new technologies must be cost-effective in order for them to be used more widely. Regardless of the mortality and morbidity associated with AL, recent economic assessments suggest that,, hospital admission costs may increase between € 11,900 [49] and € 20,300 [50] directly associated with AL complications, and these costs do not include subsequent additional
costs related to recanalization, stoma care and to the loss of productivity related to the patient, post discharge. The cost for five years of these endoscopic systems is approximately € 110,000, while the cost of the ICG for three vials is approximately € 130. This shows that if NIR-ICG proved to be truly effective in reducing AL complications, the costs of the technology would be more than adequatelycovered. The quantitative definition of adequate or inadequate bowel perfusion remains poorly defined, because none of the laparoscopic ICG-FI systems currently available are able to quantify the fluorescent signal. Even if the operator reports a positive visual evaluation, a better standardization in the interpretation of the signal would allow for a more objective evaluation.
Indeed, the kinetic analysis of the maximum intensity signal could also reveal non-arterial perfusion effects (such as venous return). Automated analysis software programs for more precise and objective quantification have recently been developed [51, 52] and NIR-ICG systems with quantitative evaluation software are likely to soon enter the market.
Targeted fluorophores activated by specific cells or microenvironments (perhaps local tissue pH, hypoxia, lactate or other metabolites) are in development [53] and could allow a more precise identification of tissues [54] than ICG. Other experimental techniques have been described to evaluate the blood supply and the integrity of the anastomosis. These include intraoperative endoscopy, pulse oximetry, Doppler ultrasound and Doppler flowmetry, intramucous pH measurement, visible light oxygen spectroscopy and NIR oxygen spectroscopy. None of the techniques mentioned is regularly used, mainly due to its complexity and its high variability of measurements [55–57].
In this regard, Barberio M. et al. [58] analyzed quantitatively, in an animal model, intestinal perfusion with fluorescence-based enhanced reality (FLER) compared with Hyperspectral imaging (HSI).
HSI is another optical imaging technique that combines a spectroscope and a camera, enabling non-contrast, real-time, qualitative and quantitative tissue analysis based on tissue oxygen saturation (StO2). The limitation of HSI in the current phase of development is the lack of adequate video speed and the absence of a system for minimally invasive surgery. In the study, HSI produced more accurate results than fluorescence angiography so that in the future this technology, if made more functional and practical, could be a useful and contrast-free intraoperative tool to quantify intestinal ischemia..
In conclusion, it is evident that further randomized controlled studies on larger and more homogeneous data are necessary to validate our findings. In the future, in order to assess more precisely the bowel perfusion with NIR-ICG fluorescence, it also needs a quantitative analysis not only of the serous layer, but also of the mucous layer. However, as many studies and trials have already highlighted, the reduction of incidence of anastomotic leakage, the evidence of a better perfusion of the bowel and, especially in emergency, the possible reduction of derivative interventions in favor of primary anastomosis are clear.