114 Chapter 5 of attention is the fact that MB can only be used in patients with adequate renal function and the intensity of the ureteral signal is influenced by the peristaltic movement of urine through the ureter 18. There are some known adverse effects after MB administration such as hypertension, dyspnea, hemolysis, methemoglobinemia, nausea and vomiting, and pain in the chest when administering doses above 2 to 7 mg/kg. Refractory hypotension and skin discoloration are known upon administration of 20 to 80 mg/kg 21. As the previous mentioned doses are much higher than needed for ureter delineation and bowel perfusion assessment as demonstrated in this study (even visible with the lowest dose of 0.25mg/kg), such adverse events are not expected for this indication. MB is currently safely used for visualization of thyroid and parathyroid glands, pancreatic neuroendocrine tumors, and breast cancer tumors and sentinel nodes within therapeutic doses of <2 mg/kg 19. The current study also demonstrated a faster washout of MB compared to ICG during bowel perfusion assessment, which is known to remain fluorescent for long periods after dye administration. This finding may allow for repeated MB bolus administrations within the same procedure for the purpose of perfusion assessment. We hypothesize that three MB dye characteristics could play a role in the faster washout. First, the molecular weight of both dyes is different, which may result in a difference of diffusion of the dyes into the capillaries; MB has a molecular weight of 319.85 Da as compared to 774.963 Da for ICG 22. Secondly, MB is more hydrophobic than ICG, which has two hydrophobic and two hydrophilic molecule groups 23-25. Thirdly, the binding properties of both dyes are probably different: ICG tends to bind to plasma proteins 26, whilst this is not well described for MB. An earlier MB washout time can be beneficial, as a repeated dye injection for bowel perfusion assessment may be necessary during a surgical procedure. When MB is completely washed out, a second dose can be given without the interference of previous signals. We also observed a difference between the washout time of an MB dose of 0.5 and 0.25 mg/kg (50 and 40 minutes respectively). The differences observed in both pigs are probably due to the MB dose administered. A recent clinical pilot study successfully demonstrated that it is feasible to delineate the ureters with MB and assess the perfusion with ICG using the same camera system 27. The authors included 12 patients who underwent complex open or laparoscopic colorectal surgeries and demonstrated successful ureteral delineation with MB in 91.6% of cases, and successful bowel perfusion assessment with ICG in all cases. In this pilot study, all measurements were only taken immediately after dye injection, without a follow-up in time. Besides, bowel perfusion was not visualized with MB. We believe, as demonstrated in our study, that the next step would be to focus only on MB fluorescence imaging for ureteral and perfusion imaging. The relatively fast washout of the MB dye may allow for repeated MB administration; one prior to the surgical procedure for ureteral imaging and one during the procedure for perfusion imaging. Based on the results of this study and previous articles in the literature, we have designed a further animal study in which intestinal perfusion quantification for MB compared to ICG will be explored in more detail.
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