Discussion
Body composition assessment in surgical patients has recently gained attention due to the possible clinical implications in developing complications and for long-term survival. For example, low skeletal muscle mass seem to be strongly associated with poor post-operative outcomes especially in cancer patients15–17. Reduced skeletal muscle mass may promote the development of a pro-inflammatory environment, basically through onset of insulin resistance,18 which is responsible for enhanced SSR after colorectal resection 4. Similarly, insulin resistance and higher levels of pro-inflammatory cytokines such as IL-6 and TNF-α are associated with abnormal adipose tissue accumulation, in particular excess of visceral adipocytes 19. Although the chronic systemic inflammation which characterizes VO is a well-known risk factor for development of several diseases associated with metabolic syndrome19,20, the role of VO in worsening surgical outcomes is still debated 19,21,22. Little is known about the role of VO on acute inflammatory response after colorectal resection. Our study aimed to characterize the magnitude of SSR after laparoscopic colorectal resection according to VO, trying to assess its role in development of infectious complications. We hypothesized that VO patients presented higher degree of SSR, thus requiring separate cut-offs for predicting safe discharge on POD3.
Although procalcitonin (PCT) presents higher specificity than CRP in differentiating between inflammation and infection 23, its use in the clinical practice after colorectal surgery is still limited, and mostly influenced development of severe bacterial infections 23–25.We therefore chose CRP as an objective marker of SSR, due to its widespread use in clinical practice and its role as predictor of complications 2. In uncomplicated surgery, CRP is generally low on POD1, then exhibits a maximal increase on POD2 and decreases by POD3. Nonetheless, CRP further increases after POD2 in patients developing adverse events. Consequently, CRP on POD3 is widely considered a reliable marker of severe post-operative adverse events, especially infectious complications. Combined with negative clinical findings, a CRP value below the specific cut-offs on POD3 was found an important marker for allowing safe discharge 2.
The results of this study confirm our original hypothesis of an association between VO and a pro-inflammatory environment, as shown by higher baseline and post-operative CRP values in the overall population. Multivariate analysis confirmed VO as an independent risk factor for increased SSR, with higher CRP values on POD1 and 2. Interestingly, the increase in SSR was stronger in patients who did not develop infectious complications. Our results are in line with recent evidence of low SSR due to reduced surgical stress from the synergistic effect of laparoscopy and ERAS protocol 1,26. Nevertheless, whilst conversion to open surgery and surgical time are well-known factors associated with increased SSR, we demonstrate here for the first time that VO may be responsible for a larger inflammatory response after laparoscopic colorectal resection. However, this association was not confirmed in patients who developed infectious complications. We can speculate that whether VO is associated with higher SSR even in complicated cases, its effect on CRP may be concealed by the greater inflammatory response fostered by infection.
Previous studies evaluating the role of VO on SSR were carried out in patients who underwent minimally invasive esophagectomy. Doyle et al. reported altered patterns of cytokine expression in VO patients both pre- and post-operatively. Despite a heightened immune and inflammatory response, this appeared to have no clinical adverse sequelae for VO subjects 27.In accordance with these findings, Okamura et al. showed that VAT quartiles were significantly associated with CRP levels both in the overall population and in patients who did not develop post-operative infectious complications 28. Following the results of these studies, our findings confirm that VO could intensify SSR following laparoscopic colorectal resection, though VO was not responsible for worse post-operative course, since the complication rates appeared to be similar between VO and non-VO patients. Whether increased SSR in VO patients is related to higher magnitude of tissue damage, enhanced inflammatory response, or both these elements would coexist, this cannot be elucidated from the present study.
Infectious complications after colorectal surgery have a major clinical impact as they increase LOS, treatment costs and worsen long-term survival in cancer patients 29,30. When early diagnosed, they can be treated effectively, and their impact is minimized. In the era of fast-track protocols, several CRP cut-off values have been proposed to ensure safe discharge. Different thresholds has been used depending on surgical procedure and surgical approach, since the amount of normal SSR varies between open31–33 and laparoscopic surgery2,34. In our opinion, all parameters that could influence SSR should be considered when proposing CRP cut-off values for safe discharge, so that its diagnostic efficiency could be increased. Our study, following previous evidences in minimally invasive esophageal surgery 27,28, demonstrates increased SSR and CRP production after laparoscopic colorectal resection in patients with increased VAT, both in the overall population and in uncomplicated cases. Consequently, high levels of CRP at POD3 may have different clinical significance in VO and non-VO patients. Notably, avoidance to consider different thresholds for these two groups would decrease the diagnostic performance (i.e., both sensitivity and specificity) of this test. Our analysis with ROC curves demonstrated that the CRP cut-off value at POD3 after minimally invasive colorectal surgery should be differentiated according to patient’s body composition, with VO patients presenting higher threshold for safe discharge.
Our study has some limitations, which shall be mentioned. First, the sample size was relatively small since we focused on patients undergoing elective surgery with minimally invasive approach. However, this decision allowed us to analyze a more homogeneous population, thus reducing the negative effect of many other confounding factors. Second, this is a retrospective observational study conducted at a single institution. The findings presented in this paper would hence need to be validated in larger and prospective cohorts. Third, since introduction of ERAS protocol, more and more patients have been discharged before POD4, thus reducing the availability of data on CRP values on POD4 and 5.
Our paper also has many strengths. The analysis of CT images and VAT was conducted by a single researcher, with large experience in body composition analysis, who was blinded to post-operative outcomes. Then, as previously mentioned, we selected a homogeneous cohort that limited the differences in clinical, pathological, and surgical variables between the two groups. Moreover, to our knowledge, this is one of the few studies analyzing the impact of VAT and VO on SSR after surgery, and it is the sole to consider patients undergoing minimally invasive colorectal resections.
In conclusion, our findings seemingly confirm the presence of a proinflammatory environment before surgery, highlighting enhanced SSR in VO patients. This increased inflammatory response was significant in the overall population and in patients without infectious complications, whilst our analysis failed to find significant difference in those who developed infectious complications. Interestingly, despite the SSR was increased in VO patients, no differences in post-operative complications could be found. We also confirmed that CRP measured on POD3 may present high sensitivity and specificity in predicting infectious complications, though different cut-off values should be considered for VO and non-VO. Future studies in larger cohorts should hence aim at elucidating the relationship between VAT, increased SSR, and incidence of post-operative complications.
Acknowledgments : none
Statement of authorship: Conti C., Pedrazzani C., Lippi G., Ruzzenente A., and Guglielmi A., provided study concept and design; Conti C., Turri G., Zamboni G.A., Gecchele G. and Valdegamberi A. collected data; Pedrazzani C., Conti C. Ruzzenente A., Lippi G., and Valdegamberi A. performed data analysis and interpretation; Pedrazzani C., Conti C., and Turri G. drafted the manuscript; Turri G., Gecchele G., Zamboni G.A., Valdegamberi A., Ruzzenente A., Lippi G., and Guglielmi A. provided critical revision of the paper.
All authors read and approved the final version of this manuscript.