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.