Comparing different pneumoperitoneum (12 vs. 15 mmHg) pressures with cytokine analysis to evaluate clinical outcomes in patients undergoing robotic‐assisted laparoscopic radical cystectomy and intracorporeal robotic urinary diversion

Abstract Background Robotic cystectomy is the mainstay surgical intervention for treatment‐refractory nonmuscle‐invasive and muscle‐invasive bladder cancer. However, paralytic ileus may complicate the postoperative recovery and may be a consequence of an inflammatory response associated with transient gut ischaemia. We have therefore investigated clinical, operative and inflammatory biomarker associations between paralytic ileus in the context of robotic cystectomy and intracorporeal ileal conduit urinary diversion. Methods Prospective consective patients referred for robotic cystectomy were consented and included in the study, while patients >75 years old and converted to open procedure were excluded. The pneumoperitoneum pressure (PP) for carbon dioxide insufflation required to perform the procedure efficiently and safely was recorded (12 or 15 mmHg). We also recorded the postoperative days patients passed flatus and stools, whether they developed ileus, as well as other standard clinical and demographic data. The expression of select proinflammatory and anti‐inflammatory cytokines was determined by multiplex analysis using a cytometric bead array with changes in profiles correlated with the pressures applied and with the existence of an ileus. Results Twenty‐seven patients were recruited, but only 20 were used in the study with 10 patients in each PP group. Seven patients were excluded all of whom had an extracorporeal ileal conduit formation. There were differences in the 40‐min shorter operative time and 1 day shorter length of stay, as well as passing flatus 1 day and stools 1.5 days earlier in the 12 mmHg compared with the 15 mmHg group. More patients had ileus in the 15 mmHg group vs 12 mmHg group (30% vs. 10.0%). These were not statistically significant. Similarly, there were no statistical differences in the expression of proinflammatory cytokines at the two different pressures or between patient groups, but there were outliers, with the median indicating nonsymmetrical distribution. By comparison, anti‐inflammatory cytokines showed some significant differences between groups, with IL‐6 and IL‐10 showing elevated levels postsurgery. No statistical difference was observed between pressures or the existence of an ileus, but the maximum levels of IL‐6 and IL‐10 detected in some patients reflect a pressure difference. Conclusions The initial findings of this novel scientific study indicated a higher risk of paralytic ileus postrobotic cystectomy and robotic intracorporeal urinary diversion when a higher pressure of 15 mmHg is used compared with 12 mmHg. Although further studies are required to establish the linkage between cytokine profile expression, pressure and ileus, our initial data reinforces the advantages of lower pressure robotic cystectomy and intracorporeal urinary diversion in patient outcomes.

patients had ileus in the 15 mmHg group vs 12 mmHg group (30% vs. 10.0%). These were not statistically significant. Similarly, there were no statistical differences in the expression of proinflammatory cytokines at the two different pressures or between patient groups, but there were outliers, with the median indicating nonsymmetrical distribution. By comparison, anti-inflammatory cytokines showed some significant differences between groups, with IL-6 and IL-10 showing elevated levels postsurgery. No statistical difference was observed between pressures or the existence of an ileus, but the maximum levels of IL-6 and IL-10 detected in some patients reflect a pressure difference.
Conclusions: The initial findings of this novel scientific study indicated a higher risk of paralytic ileus postrobotic cystectomy and robotic intracorporeal urinary diversion when a higher pressure of 15 mmHg is used compared with 12 mmHg. Although further studies are required to establish the linkage between cytokine profile expression, pressure and ileus, our initial data reinforces the advantages of lower pressure robotic cystectomy and intracorporeal urinary diversion in patient outcomes. The pathophysiology of postoperative ileus in the context of robot-assisted laparoscopic surgery is multifactorial. Laparoscopic surgery requires abdominal insufflation of gas and establishing a certain pneumoperitoneum pressure (PP) which can precipitate compromised mesenteric vascularity and gut ischaemia. 3 There are studies emerging in robot-assisted laparoscopic radical prostatectomies (RALPs), highlighting enhanced operative and postoperative recovery outcomes including reduced rates of ileus with lower PP. 4,5 Transient gut ischaemia has been associated with the development of postoperative ileus. 6 RARCs and RALPs being performed in the steep Trendelenburg position may also potentiate this ischaemia.
Furthermore, alterations in gut vascularity promote shifts in the gut barrier and microbiome, causing bacterial translocation and endotoxin release. 7 This raises an inflammatory response, mediated by local and distant humoral factors including cytokines. Indeed, alterations in serum 8 and peritoneal exudate cytokine levels 9 have been associated with ileus, suggesting a relationship for further investigation. In this regard, previous studies have shown a reduction in proinflammatory cytokines and an increase in anti-inflammatory cytokines in robotassisted cystectomy and abdominal surgery, 10,11 associated with a decrease in tissue damage and associated cytokine storm. 12,13 Furthermore, low-pressure robotic surgery has been shown to improve patient outcomes and is associated with a decrease in surgical injury. 14 With growing evidence of low-pressure robotic surgery impacting patient outcomes positively, we carried out a study comparing PPs in RARCs and investigated whether high pressure was associated with ileus and with changes in cytokine expression with the aim of using the latter as potential biomarkers for timely management and patient recovery.    Cytokine analysis was carried out using the BD™ CBA Human '0' and meeting the BMI cut-off for 'overweight'. None of these differences were statistically significant.

| METHODS
The oncological data for the cohort and PP groups ( Table 2) show that most patients in the cohort had Ta/T1 disease, with a slightly higher proportion of T2 disease in the 12 mmHg group.
These were all high-grade transitional cell carcinomas, with more   Cytokine analysis show that the median values for the proinflammatory molecules TNFα, IFNγ, IL-1β, IL-2 and IL-17A were not significantly altered either by pressure differences (Table 3) or between the five patient groups (Figure 2A Table 3).

| DISCUSSION AND CONCLUSIONS
Our data highlight interesting trends in perioperative outcomes with lower PP in RARC and add to the growing body of evidence favouring lower PP robotic, as well as laparoscopic surgery in general. We highlight faster passage of flatus and stools and reduced risk of ileus in 12 versus 15 mmHg. The lower PP was also associated with shorter LOS, more blood loss and quicker operative time.
Interestingly, postoperative complication rates and resultant admission were not different between the groups. While not statistically significant, these trends which corroborate other findings from other studies are promising and may relate to the smaller study sample size.
A US unit retrospectively reviewed records of N = 200 consecutive RALPs to investigate operative parameters and postoperative outcomes between 12 and 15 mmHg PPs (1:1 subject ratio). 15 They found that 12 mmHg was also associated with less ileus (4% vs. 8%, statistically nonsignificant). Additionally, operative times were slightly quicker with lower pressures; and complication and readmission rates were similar across PPs. Retrospective data from the same unit supported these findings, with more patient numbers. 16  Another US study looking again at consecutive RALPs, but this time at an even lower pressure of 6 (N = 300) versus 15 mmHg (N = 300) show significant promise. 4 The lower pressure group was also associated with 20 mL more blood loss, shorter LOS (0.5 vs. 1 days) and same day discharges (43.3% vs. 0, all P < 0.001). Only one patient had ileus in their cohort (15 mmHg  Our unit carried out a similar study investigating operative, clinicdemographic and oncological differences between PPs in robotic prostatectomies in N = 10 patients. We also found that lower pressures were associated with reduced rates of ileus, and furthermore, this was associated with alterations in postoperative cytokine levels favouring an anti-inflammatory response. 22 The latter has not been explicitly confirmed in the current study, with the medians for IL-1β, IL-2, IL-17A, TNFα and IFNγ showing no statistically significant differences between pressures or study groups.
Unlike the proinflammatory cytokines, IL-6 and IL-10 were expressed at low levels presurgery but increased significantly immediately postsurgery, peaking 2 h after and remained partially elevated over 24 h. As with the proinflammatory cytokines, we have not demonstrated a statistical difference between levels at 12 and 15 mmHg pressures which may be due to large variabilities in the expression of cytokines amongst individuals within cohorts and to the small numbers of participants in each group. This therefore warrants a larger study that is powered to ensure statistical differences can be clearly demonstrated. We acknowledge that in our pilot study, we have not looked into pain score and will be in future planned trials.
We acknowledge the limitations in our study including limited numbers of 20 patients only but a larger multicentre is currently in preparation where the impact of different PPs during RARC and intracorporeal robotic urinary diversion. Oncological follow-up is currently at 12 months, reassuringly no disease recurrence has been identified but longer data collection will continue.
Low-pressure robotic surgery shows promising positive trends in operative and postoperative recovery parameters. 23