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ORIGINAL
Serum C-reactive protein level on first postoperative day can
predict occurrence of postoperative pancreatic fistula
after laparoscopic gastrectomy
Shinichiro Yamada1,2, Shigehiko Yagi1, Koichi Sato1, Mikiya Shin’e1, Akimasa Sakamoto1, Daichi Utsunomiya1,
Shohei Okikawa1, Norimasa Aibara1, Miya Watanabe1, Masayoshi Obatake1, Riki Ono1, Masahiko Fujii1,
Hiromi Otani1, and Hideki Kawasaki1
1

Departments of Gastrointestinal Surgery, Ehime Prefectural Central Hospital, Matsuyama, Japan
Department of Surgery, Tokushima University, Tokushima, Japan

2

Abstract : Purpose : Postoperative pancreatic fistula (POPF) is a serious complication after gastrectomy for gastric cancer. The purpose of this study is to identify the risk factor of POPF and evaluate C-reactive protein on
postoperative day 1 (POD1) as the predictor for POPF after laparoscopic gastrectomy (LG). Methods : Between
May 2013 and September 2016, 226 patients who underwent LG for gastric cancer were investigated. Patientswere divided into 2 groups; POPF group (n = 17) and control group (n = 209). Clinicopathological factors werecompared between 2 groups. Results : In POPF group, there are more male patients (p = 0.003) compared with
control group. Preoperative factors, such as age, BMI, and prevalence of previous operation and comorbidity
showed no significant difference between 2 groups. Regarding tumor factors and perioperative data such as
blood loss and operative time, there were also no significant difference between 2 groups. POPF group showed
longer postoperative hospital stay, and higher serum CRP level on POD1 (p < 0.0001). Multivariate analysis revealed that high CRP level on POD1 ( ≥ 3mg/dl) was independent risk factor of POPF. Conclusions : High serum
CRP level on POD1 can predict the occurrence of POPF. J. Med. Invest. 66 : 285-288, August, 2019
Keywords : laparoscopic gastrectomy, postoperative pancreatic fistula, C-reactive protein

INTRODUCTION
Laparoscopic gastrectomy (LG) has been reported to be related with reduced intraoperative bleeding, less postoperative
pain, and earlier recovery of bowel movements compared with
open gastrectomy (1-3). As Japanese gastric cancer treatment
guidelines recommend laparoscopic assisted distal gastrectomy(LADG) as well as open distal gastrectomy for the treatment ofclinical stage I gastric cancer (4), LG is now widely used, andnumber of patients who undergo LG may continue to increase,especially in Japan.
Gastrectomy has been performed with lower mortality andmorbidity rate recently because of advances in surgical techniques, devices, and perioperative management (5-7). However,intraperitoneal bleeding and abdominal abscess caused bypostoperative pancreatic fistula (POPF) is the most serious
postoperative complications. Though POPF is usually treatedafter an abscess has formed, accurate prediction of severe POPF
in the early postoperative period would provide a chance to treat
appropriately. If POPF could be predicted in early postoperative
period, abscess formation might be preventable due to early
therapeutic interventions such as administration of appropriate
antibiotics and drainage of excess fluid (8). Recent studies haveindicated that perioperative systemic inflammatory responses
can predict postoperative complications in various types of cancer (9-11). It has been reported that C-reactive protein (CRP) on
Received for publication November 26, 2018 ; accepted May 23, 2019.
Address correspondence and reprint requests to Shinichiro Yamada,
M.D. PhD. FACS., Department of Surgery, Tokushima University,
3-18-15 kuramoto-cho, Tokushima, 770-8503, Japan and Fax : +8188-631-9698.

postoperative day (POD) 1 might be able to predict the occurrence of POPF after pancreatectomy (12). However, it is unclearthat early postoperative inflammatory response, such as CRP on
POD1 can predict the occurrence of POPF after LG. We hypothesized that the early inflammatory response might be related tothe development of PF after LG. In this study we retrospectively
investigated perioperative clinical variables, including CRP on
POD1 as predictors of postoperative PF.

PATIENTS AND METHODS
Between May 2013 to September 2016, 226 patients underwent laparoscopic gastrectomy for gastric cancer in Ehime
Prefectural Central Hospital. Patients underwent preoperative
assessments, including gastric endoscopy, computed tomography(CT) scans, and laboratory tests. Clinical stages, D categories
indicating the extent of lymph node dissection and other clinicopathological features were classified according to the JapaneseClassification of Gastric Carcinoma 3rd English edition (13).
During gastrectomy, we inserted a drainage tube above the pancreas or behind the anastomosis. The amylase concentration in
the drainage fluid was measured on POD 1 and POD 3. Pancreatic fistula (PF) was defined according to the ISGPF definition(14) : output via an operatively placed drain of any measurable
volume of drainage fluid on or after POD3, with an amylase concentration more than three times higher than the upper normal
serum value. it was classified into three categories : transientpancreatic fistula (no clinical impact) (grade A) ; requiring achange in management or adjustment in the clinical pathway(grade B) ; requires a major change in clinical management or
deviation from the normal clinical pathway (grade C). In thisstudy, grade B (n = 16) and C (n = 1) are defined as “postoperative

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S. Yamada, et al. Prediction of POPF using CRP after LG

PF (POPF)”. Patients were divided into 2 groups ; POPF group(n = 17) and control group (n = 209), including grade A PF (n = 9).
This study was approved by the Institutional Review Board of
Ehime Prefectural Central Hospital (No. 30-56).

STATISTICAL ANALYSISThe chi-squared test for categorical variables and the Mann–
Whitney U test for continuous variables were used to compare
clinicopathological variables between the two groups. A receiver
operating characteristic (ROC) curve was created to identify
the best cutoff value of CRP on POD1 for evaluating the risk of
POPF. A multivariate logistic regression model was used to detect independent predicting factor for POPF. Variables achieving
P < 0.05 in the univariate analysis were included in the multivariate analysis. All statistical analysis was performed using
statistical software (JMP 8.0.1., SAS Campus Drive, Cary, NC).
P < 0.05 was considered significant.

group. POPF group had significantly more male patients comparedwith control group (p < 0.05). Other factors including age, BMI,
incidence of previous operation, and comorbidities such as diabetes mellitus, cardiopulmonary disease, and chronic renal failure
with dialysis showed no significant difference between two
groups. Regarding tumor and operative factors, tumor diameter,
histological type, T/N factors, extent of lymph node dissection,
intraoperative bleeding, and operative time also showed no significant difference between two groups. However, CRP level on
POD1 was significantly higher in POPF group compared with
control group (p < 0.01). To determine the cut off value of CRP for
prediction of POPF, ROC curve analysis was performed. (Figure1), and cut off value of CRP on POD1 was set as 3mg/dl. Area
under the curve (AUC) was 0.783. Furthermore, postoperative
hospital stay was significantly longer in POPF group comparedwith control group (p < 0.01). Figure 2 showed comparison of
CRP level on POD1 among three groups ; no POPF (n = 200),
Grade A POPF (n = 9), and Grade B/C POPF (n = 17). Although

RESULTS
Table 1 summarizes the univariate analysis with clinicopathological variables of patients in the POPF group and control

Table 1 preoperative data of POPF group and control group withgastric cancer who underwent curative gastrectomy

BMI : Body mass index ; CRP : C-reactive protein ; POD : Postoperative day
The chi-squared test for categorical variables and the Mann–
Whitney U test for continuous variables were used to compare
clinicopathological variables between the two groups.

Figure 1. A ROC curve identified the cutoff value of the serum CRP
level on POD1 to be 3.04 mg/dl in case with POPF. Area under the
curve was 0.783.

p<0.0001(mg/dl)p=0.1712

p=0.12

10
CRP on POD1

< Patients’ background >POPF (n = 17) control (n = 209) p-valueAge (years)
72.3 ± 10.9
69.2 ± 11.8
0.29
Gender0.003
Male
16 (94.1%)
119 (56.9%)
Female1 (5.9%)90 (43.1%)
22.9±2.2
22.4±3.4
0.48
BMI (kg/m2)
Previous operation
2 (11.8%)
64 (30.6%)
0.17
Preoperative complication
Diabetes Mellitus
3 (17.6%)
29 (13.9%)
0.67
Cardiovascular disease 3 (17.6%)
17 (8.1%)
0.18
CKD with dialysis
0 (0%)
5 (2.4%)
0.52< Perioperative factor >Type of gastrectomy
0.80
Distal15 (88.2%)
187 (89.5%)
Total
2 (11.8%)
22 (10.5%)
Tumor diameter (mm)40.4 ± 23.5
33.7 ± 20.1
0.19
Histological type
0.36
tub
13 (76.5%)
134 (64.1%)
por, sig
4 (23.5%)
75 (35.9%)
pT
0.45
pT1
6 (35.3%)
56 (26.8%)
pT2-4
11 (64.7%)
153 (73.2%)
pN
0.16
pN0
2 (11.8%)
57 (27.3%)
pN1-3
15 (88.2%)
152 (72.7%)
Lymph node dissection
0.14
D2
8 (47.1%)
63 (30.1%)
D0, 1, 1+
9 (52.9%)
146 (69.9%)
Intraoperative bleeding (ml) 78.7±117.7
63.5±94.0
0.53
Operation time (min)215±49215±51
0.98
CRP on POD1 (mg/dl)
6.03±4.89
3.31±1.86<0.0001
Postoperative hospital stay (day) 23±1813±9<0.00018
6
4
2
0

no-POPF(n=200)

Grade A
(n=9)

Grade B/C
(n=17)

Figure 2. Comparison of CRP level on POD1 among no POPF group,

Grade A POPF group, and Grade B/C POPF group. CRP of Grade B/
C POPF group was significantly higher than that of no POPF group(p < 0.0001). CRP of Grade A tended to be higher compared with thatof no PF group (p = 0.17), and CRP of Grade B/C tended to be higher
compared with that of Grade A (p =0.12). CRP level was compared byMann–Whitney U test.

The Journal of Medical Investigation Vol. 66 August 2019
there was no significant difference, CRP of Grade A tended to behigher compared with that of no PF group (p = 0.17), and CRP of
Grade B/C tended to be higher compared with that of Grade A(p = 0.12). With factors which were detected in univariate analysis (male gender, CRP on POD1 ≥ 3mg/dl), multivariate analysis
was performed (table 2). High CRP on POD1 (≥ 3mg/dl) was independent predictive factor of POPF (p = 0.02). Male gender tended
to be independent predictive factor (p = 0.08).

Table 2 Multivariate logistic analysis of risk factors for postoperative pancreatic fistula

95% confidence interval p value

Parameters

Odds ratio

Gender (male)

6.491

0.818 - 51.474

0.08

CRP on POD1 ≥ 3mg/dl

11.5961.480 – 90.862

0.02

DISCUSSION
In this study, we have revealed that high CRP level on POD1(≥ 3mg/dl) was independent risk factor of POPF. CRP on POD1
may be able to predict the occurrence of POPF. Male gendertended to be independent risk factor of POPF. It has been reported that the risk factors for POPF were high BMI, large visceralfat area, extended lymphadenectomy, splenectomy, male sex,
and the presence of comorbidities (15-20). Operative factors havebeen also reported to be important for risk factors of POPF. Ida
et al. revealed that pancreatic compression by the assistant’s
forceps can contribute to pancreatic juice leakage using fluorescence imaging in swine model (21). We perform LG in team with
fixed member, and shear consciousness that assistants should
pay attention to retract the pancreas carefully and gently withgauze. Additionally, ultrasonic coagulating and cutting devices
are recently used for supra-pancreatic lymph node dissectionin LG. The laparoscopic operation makes the cutting lines forsupra-pancreatic lymphadenectomy to be closer to the edge of thepancreas due to the magnified view, which has possibility of heat
injury. Operators should pay attention not to cause heat injury to
the pancreas when handling ultrasonic coagulating and cutting
devices (22, 23).
It is important to detect signs of POPF and its related complication in the early postoperative period and to perform appropriate management because POPF can cause serious complications
including intra-abdominal bleeding and severe inflammation
with abscess formation. Apparent peripancreatic abscesses due
to POPF are related to an increased white blood cell count,
neutrophil count, and serum CRP level (24). Because leakageof pancreatic juice occurs during operation, inflammatory response may be enhanced at the early stage of postoperative
period when leakage is massive, which correlate with severe PF.
It was also reported that CRP on POD1 after pancreatectomy
could be independent risk factor for PF (10). Therefore, in thisstudy, we focused on detection of POPF in early postoperative
period. Kobayashi et al. reported that CRP level on POD 3 after
gastrectomy can predict POPF after gastrectomy (25). However,
CRP level on POD 1 showed no significant difference between
severe POPF patients and other patients. Because their study
design included open gastrectomy, CRP level on POD 1 seemed
to be higher even in patients without POPF. Matsunaga et al. also
showed that CRP level on POD3 is predictive indicator of POPF
after LG (24). In their study CRP level on POD 1 also showed nosignificant difference between POPF group and no-POPF group.
Longer operation time than our study may relate with relatively

287high CRP in no-POPF group. As POPF can be apparently diagnosed on POD3 along with ISGPF definition (14), predictor inearlier postoperative period is necessary to perform appropriate
management for POPF. CRP level on POD 1 after LG may enable us to perform more therapeutic postoperative management
after gastrectomy, such as observation with lower threshold for
CT scan, preservation of drainage tube and prolonged usage ofantibiotics. In contrast, patients without elevation of CRP levelmay be eligible for early removal of drainage tubes from thepoint of view of enhanced recovery after surgery and avoidanceof retrograde infection (25).
To our knowledge, this is the first report which revealed that
CRP on POD1 may be a predictive factor for POPF after LG.
However, our study has several limitations. First, this study wasa retrospective design, and the number of patients with severe
PPF was small. Second, there is still no standard definition ofsevere POPF. Though several studies of pancreatic surgery haveused a definition of Grade C PF based on the ISGPF classification (26-28), the number of patients with this severity of gastricsurgery is small. Indeed, our study had only one patient with
Grade C POPF. So, we defined POPF as Grade B and C PF.
In conclusion, high CRP level on POD1 (≥ 3mg/dl) was independent risk factor of POPF after LG. High serum CRP level on
POD1 may be able to predict the occurrence of POPF.
We disclose no commercial interest that they may have inthe subject of study and the source of no financial or material
support.

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