Research Article

Clinical Impact of the Perioperative Inflammatory Status in Pancreatic Surgery: Data from a High-Volume Center

Matteo De P1*, Paiella S1, Ciprani D1, Landoni L1, Salvia R1, Fumagalli L2 and Bassi C1
1Department of General and Pancreatic Surgery, University and Hospital Trust of Verona, Italy
2Department of General Surgery, Hospital of Lecco, Lecco, Italy

*Corresponding author: Matteo De P, Department of General and Pancreatic Surgery, Pancreas Institute, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy

Published: 20 Sep, 2018
Cite this article as: Matteo De P, Paiella S, Ciprani D, Landoni L, Salvia R, Fumagalli L, et al. Clinical Impact of the Perioperative Inflammatory Status in Pancreatic Surgery: Data from a High-Volume Center. Clin Surg. 2018; 3: 2121.


Purposes: The inflammatory status is related to postoperative outcomes, and its response to surgical trauma is a significant determinant of surgical outcome, especially for infectious postoperative complications. This study aims to analyze the relationship between the immune and inflammatory indexes, assessed perioperatively, and the postoperative course after pancreatic surgery.
Methods: Data of consecutive pancreatoduodenectomies and total pancreatectomies performed at the General and Pancreatic Surgery Department of Verona from 2014 to 2016 were retrieved from a prospectively maintained electronic database and evaluated. Perioperative variations of blood count cells were recorded and then compared with postoperative outcomes.
Results: The final population consisted of 554 patients. Post Operative Pancreatic Fistula (POPF), infectious complications, major complications, and mortality occurred in 75(13.5%), 261(47.1%), 85(15.3%), and 17(3%) patients, respectively. Patients with absolute and median postoperative low lymphocyte counts were associated with a worse postoperative clinical course (p<0.05). Furthermore, a preoperative Systemic-Immune-Inflammation Index (SIII) higher than 900 correlated with mortality.
Conclusion: The unpaired recovery of immune effectors in the early postoperative days, expressed by low lymphocyte count and a high preoperative SIII are associated with a complicated postoperative course.
Keywords: Pancreaticoduodenectomy; Total pancreatectomy; Systemic-immune-inflammation index; Infectious complications; Lymphocyte count


The morbidity and mortality rates after pancreatic surgery are still high. Post Operative Pancreatic Fistula (POPF) and Infectious Complications (ICs) are the most threatening complications of pancreatic resections [1,2]. Whilst POPF is usually related to pancreatic texture, main pancreatic duct size and intraoperative variables [3], on the other hand, the impact of ICs on postoperative course might be related to an impairment of pro- and anti-inflammatory processes that could ultimately lead to the development of infectious events. The direct association between ICs and patients' immune impairment has been already described [4]. The hosts’ immune response to tissue injury and surgery is complex and poorly understood, especially during major surgery such as pancreatic resections. Up to now, the host response was believed to follow a bimodal response, with a subtle equilibrium between systemic inflammatory and anti-inflammatory response syndromes [5]. Recent data, however, suggest that his paradigm may not be correct [6]. The physical stress related to surgical increases the expression of T-helper 2 lymphocytes which causes an impaired cell-mediated immunity. Then, the activation of the hypothalamic-pituitary-adrenal axis and the sympatho-adrenal system with the release of cortisol and catecholamines appear to be responsible for the alteration of the lymphocyte count [7]. Furthermore, the activation of the hypothalamic-pituitary-adrenal axis generates a rapid and massive influx in bloodstream of neutrophil granulocytes mobilized by the spleen, a depletion of blood lymphocytes by homing from blood into lymphatic organs (bone marrow, nodes and gut) and their recovery in peripheral blood from 36 hrs to 72 hrs after surgery [8,9]. Furthermore, the increased expression of arginase-1, due to the pro-inflammatory cytokines, causes an arginine deficient state, which further impairs the functions of the lymphocytes [10]. Recently, the Systemic-Immune-Inflammation Index (SIII), based on lymphocyte, neutrophils, and platelet counts, has been described as a predictor of survival in patients affected by pancreatic cancer [11,12]. In this setting, major complications and, particularly, ICs might be related to an impaired immune response of the patient, with an impaired immune host response. This study aimed to analyze the relationship between perioperative blood cell count patterns and surgical outcomes of patients submitted to pancreatic surgery.

Table 1

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Table 1
Demographic data.


The study was conducted, after the Institutional Review Board approval (CESC-VR 1101), according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [13]. The Institutional electronic prospectively maintained database was queried and all consecutive Pancreatoduodenectomies (PD) and Total Pancreatectomies (TP) performed from 2014 to 2016 were retrieved. An observational study was conducted collecting clinical and laboratory data of patients submitted to pancreatic resection. Demographic and clinical details included age, gender, ASA score, Body Mass Index (BMI), diabetes mellitus, Charlson Age-adjusted Comorbidity Score Index (CACI) [14], jaundice, and preoperative biliary drain. Blood cell counts were taken at baseline and on postoperative days 1,2 and 3. All blood cell counts were performed with the automated counter. Furthermore, the median value of each differential cell type was calculated through the values collected on postoperative days 1,2 and 3. The SIII was defined as platelet count multiplied by neutrophil-to-lymphocyte ratio (absolute neutrophil count divided by absolute lymphocyte count). POPF was recorded according to the updated ISGPS definition, and only grades B and C were considered [15]. All postoperative complications and mortality rates were collected at 90th postoperative day and graded according to Clavien-Dindo classification [16]. Major complications were defined as a Clavien-Dindo grade higher than 3. Infectious Complications (IC) included SSI, septic events, pneumonia, urinary tract infections and blood infections. ICs were also considered as those clinical conditions related to infection by bacterium or fungi in a specific organ/compartment when this was demonstrated bacteriologically by positive cultures. Statistical analyses were performed using SPSS software® version 22.0 (IBM corp., Armonk, NY, USA). Normally distributed data were presented as mean with Standard Deviation (SD) and non-normally distributed data were presented as median with Interquartile Range (IQR). Categorical variables were presented as counts and proportions. The group differences were assessed using a Chi-square test or Fisher's exact test for categorical variables. For non-normally distributed continuous variables the Mann-Whitney U test was applied. Factors found to be a value of p ≤ 0.05 on univariate analysis were subjected to multivariate analysis with logistic regression models. The p values were presented as odds ratios or hazard ratios and 95% CIs, as appropriate. Statistical significance was determined by a p-value of <0.05.


A total of 648 patients were submitted to pancreatic resection, PDs and TPs, during the study period. The perioperative clinical and laboratory data were available only on 554 (85.5%) patients that were the final population. (Table 1) shows demographic and pathological data. POPF occurred in 75 (13.5%) patients. The analysis of the risk factors for the development of POPF is shown in (Table 2). The absolute preoperative lymphocyte count, the absolute neutrophil and lymphocyte count on POD II, and the median of postoperative lymphocyte count were correlated to POPF (p<0.05). The absolute lymphocyte count on POD II was also associated with the development of ICs (p=0.032), as reported in (Table 3). The absolute white blood cell, the neutrophil and lymphocytes count, as well as the median postoperative lymphocyte count were related to the occurrence of major complication and mortality (p<0.05), as showed in (Table 4 and 5). Furthermore, the mortality rate was increased in patient with a preoperative SIII higher than 900 (p=0.039). The multivariate analysis presented in (Table 6) shows that a low lymphocyte counts on POD II and a low median of postoperative lymphocyte count were independent risk factors for the development of a complicated postoperative course.


The occurrence of complications after pancreatic surgery is a suffering event. Despite the improved surgical technique, the accurate preoperative patient selection, and the strict postoperative surveillance, the overall morbidity and mortality rates are still high [17]. Some variables are well known risk factors for the development of postoperative complications after pancreatic surgery (a small main pancreatic duct size, a soft gland texture, the presence of jaundice and/ or biliary stent) [3,18]. Other risk factors are mainly patient-related, such as performance status, body mass index, and the presence of comorbidities [19]. The study reports a postoperative absolute low lymphocyte count and a low median lymphocyte count are risk factors for the development of POPF, major complication, ICs and mortality. These data are in line with the literature [20]. Particularly, the variations of lymphocytemia seem to represent an interesting marker of the host response following surgery [21]. Generally, the activation of the hypothalamus-pituitary gland-adrenal gland axis following the surgical trauma generates the acute lymphocytopenia occurring in the early postoperative days, with a restore in 24 hrs to 36 hrs after surgery [9,22]. The data of the literature, confirmed by this series, could be explained by an ineffective host response to the surgical trauma due to a single pathway failure, such as a deficient gene expression of gammac cytokines [23] or alterations of a suppressor of cytokine signaling family of proteins [21], or evenly to a multisystem failure that involving the autonomic nervous, the endocrine, and immune system [24]. In patients suffering from cancer, the perioperative inflammatory status, e.g. the blood lymphocyte counts and the SIII, is a strong predictor of survival [12,25]. Clark et al. reports that in patients undergoing pancreaticoduodenectomy, a low preoperative lymphocyte count retains significance on multivariate analysis towards overall survival [26]. Fogar find that the number of circulating lymphocytes impacts on survival of pancreatic cancer patients, suggesting that the immune system plays a pivotal role in pancreatic adenocarcinoma immunesurveillance [27,28]. Our results show that SIII and lymphocytopenia are associated with postoperative mortality after pancreatic resections. This study has several limitations. First, it was carried out using a prospectively maintained database but it was retrospectively analyzed, generating information/selection bias. Second, we included either pancreaticoduodenectomy or total pancreatectomy and it might be speculated that the surgical trauma of these two surgeries is not equal, especially considering the endocrine function of the pancreas that is acutely aborted following total pancreatectomy. Third, we included either patients suffering from malignancies and not, and it is well known that in the first there is an intrinsic impairment of the immune system, due to the tumor itself. Furthermore, this subgroup of patients included subjects that received preoperative chemotherapy and this somehow might have been impacted on lymphocytes counts. Our study describes for the first time the correlation between SIII and postoperative mortality, confirming the direct role of the lymphocyte pattern on the postoperative clinical course. The perioperative identification of patients at risk of developing postoperative complications, using laboratory information easily retrievable, might allow applying a strict postoperative surveillance, with a dedicated postoperative management following pancreaticoduodenectomy and total pancreatectomy. Our results do not allow us to draw a definitive conclusion concerning the reliability of lymphocyte count changes after surgery. Conversely, our findings suggest that a further exploration of the host response to surgery, using easily available measurements, such as blood cell differential count, is worthwhile. In addition, on the basis of present and future findings, a proper analysis of the immune system before surgery could be useful to select patients that might benefit from a perioperative immune treatment, such as cytokine administration or immunonutrition, to rebalance the inflammatory status and to improve the restore of a favorable leucocytes pattern [29,30].

Table 2

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Table 2
Variables associated with the development of POPF.

Table 3

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Table 3
Variables associated with the development of Infectious Complication.

Table 4

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Table 4
Variables associated with the development of Major Complication.

Table 5

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Table 5
Variables associated with Mortality.


The unpaired recovery of immune effectors in the early postoperative days, expressed by a low lymphocyte count and a higher preoperative SIII, is associated with a complicated postoperative course and with mortality. Further exploration of the host response to surgery is needed to confirm the power of these reliable, feasible and reproducible inflammatory markers.

Table 6

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Table 6
Multivariate Analysis of predictor of postoperative complication.


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