Abstract
Background/Aim: Drains are frequently placed at the time of distal pancreatectomy (DP) to evacuate pancreatic juice and intra-abdominal exudate and obtain information on abdominal cavity status. However, the timing of drain removal remains debatable. Meanwhile, prolonged drain placement might increase the risk of postoperative pancreatic fistula (POPF), with a prevalence of 5-40%. Therefore, we examined the effect of removing the drain within postoperative day (POD) 3 on the risk of POPF development. Patients and Methods: A total of 108 consecutive patients who underwent DP between April 2015 and March 2020 were examined and divided into two groups according to the day of drain removal; hence, for some patients, the drain was removed on POD 1 (POD 1 group) and for others on POD 3 (POD 3 group). Furthermore, risk factors, including drain fluid amylase (DFA) levels, for developing POPF were investigated. Results: The overall rate of clinically relevant POPF was 4.6% and did not significantly differ between the POD 1 and POD 3 groups [4.5% and 4.9%, respectively (p=0.924)]. DFA levels on POD 1 did not significantly differ between patients with and without POPF. On POD 3 and POD 5, C-reactive protein (CRP) levels were significantly higher in patients with POPF than in those without (p=0.03 and p<0.001, respectively). Conclusion: Early drain removal regardless of DFA level may reduce the risk of developing POPF. CRP measured on POD 3 and POD 5 appeared to be a useful predictor of clinically relevant POPF.
Distal pancreatectomy (DP) is the standard surgical procedure for both benign and malignant tumors of the pancreatic body and tail. Post-DP morbidity remains high, while mortality has recently decreased due to improvements in operative techniques and perioperative management strategies (1, 2). The most serious complication is postoperative pancreatic fistula (POPF), which may be a life-threatening condition. The incidence of clinical POPF (Grade B or C) after DP ranges between 5% and 40% (3-10), which is higher than that observed following pancreatoduodenectomy (11, 12).
Drains are frequently placed to evacuate not only pancreatic juice, but also intra-abdominal bloody and lymphatic fluids and are sometimes useful in obtaining information on post-DP intra-abdominal status. Prolonged drain placement, however, might increase the risk of retrograde infection along the drain (12, 13). The indication for drain insertion and the timing of drain removal are still under debate.
Drain fluid amylase (DFA) levels have been reported to be helpful in predicting POPF and used as a criterion for drain removal (14, 15-18). Infection control, however, might be more critical than monitoring DFA levels in attempts to avoid POPF aggravation. In accordance with this concept, we introduced early removal of the drainage tubes on postoperative day (POD) 1 or POD 3 on the condition that the drain fluid is clear, regardless of the DFA level and the amount of drain fluid.
This study aims to evaluate the clinical significance of the DFA level and the amount of fluid after DP and compare the incidence of clinically significant POPF and other abdominal complications after DP between patients with drain removal on POD 1 and POD 3. Furthermore, we investigated the postoperative predictive factors of POPF in cases of drain removal within POD 3 (15-18), without considering DFA data.
Patients and Methods
Patients. We evaluated 108 consecutive patients who underwent DP at the First Department of Surgery at Yamanashi University between April 2015 and March 2020 and divided them into two groups according to the day of drain removal; some had the drain removed on POD 3 (from April 2015 to March 2017; 41 patients; POD 3 group) and some on POD 1 (from April 2017 to March 2020; 67 patients; POD 1 group). Data on clinical characteristics and pathological examinations were obtained from electronic medical records in our hospital. As a supplement to the perioperative data, the surgical and anesthetic charts of each patient were reviewed. This study was approved by the Human Research Ethics Committee of Faculty of Medicine, University of Yamanashi, Yamanashi, Japan (No. H30232).
Surgical techniques. After dissection of the peripancreatic space, the pancreas was divided using a reinforced triple-row stapler (the Endo GIA™ Reinforced Reload with Tri-Staple™ Technology 60 mm; COVIDIEN, North Haven, CT, USA). The closure jaw was clamped slowly and carefully, and the pancreas was cut little by little over a period of 15 min to reduce damage to the pancreatic parenchyma; then, the staples were applied. The stapler was not released immediately after firing. All surgeries were performed by pancreatic surgeons with more than 10 years of experience.
Drainage technique. Two closed drains were routinely inserted after DP, one into the space near the stump of the remaining pancreas and the other into the left subphrenic space in the splenic fossa. In cases of spleen-preserving distal pancreatectomy (SPDP), the left subphrenic drain was not inserted.
Perioperative management. To prevent bacterial infection, second-generation cephem antibiotics were administered both intraoperatively and for three days postoperatively. As a rule, patients were introduced to an oral diet on POD 3. Blood glucose levels were routinely measured four times a day, and if high, insulin was subcutaneously administered with a target level of 100-150 mg/dl. Drainage tubes were removed on POD 1 or POD 3 regardless of the DFA level and the amount of drain fluid, providing the drain fluid was clear, indicating absence of bacterial infection and unexpected intraoperative intestinal damage. None of the patients received prophylactic somatostatin analog therapy for POPF prophylaxis.
POPF was diagnosed according to the International Study Group of Pancreatic Fistula (ISGPF) criteria established in 2016 (19). Delayed gastric emptying (DGE) was diagnosed according to the definitions the ISGPF (20).
Statistical analysis. Data were described as means±standard deviations. Patient characteristics and intra- and perioperative factors between the two groups were compared using the Chi-square test, Fisher’s exact test, and Mann–Whitney U-test. The optimal cutoff level was determined by constructing receiver operating characteristic curves (ROC). Statistical significance was defined as a probability (p) value<0.05. Statistical analyses were performed using SPSS version 23.0 software (SPSS Inc., Chicago, IL, USA).
Results
Incidence of POPF. Our early drain removal strategy resulted in the development of five clinically relevant cases of POPF among the 108 consecutive patients. The incidence did not significantly differ between the two groups [4.5% and 4.9% for POD 1 and POD 3, respectively (p=0.924)]. The comparison revealed no significant difference in patient or intraoperative characteristics, except for the amount of blood loss and frequency of blood transfusion between the two groups (Table I). Blood loss was significantly lower in the POD 1 group than in the POD 3 group, and consequently, blood transfusion was more frequently required in the POD 3 group. The thickness of the pancreas, as measured at the resection line, did not differ between the two groups.
Characteristics of the enrolled patients according to day of drain removal (Day 1 group vs. Day 3 group).
Drain fluid amylase level and clinical courses. DFA level on POD 1 was similar for the POD 1 and POD 3 groups. White blood cell (WBC) count and C-reactive protein (CRP) levels did not significantly differ between the two groups on day 3, 5, and 7, although the DFA level tended to be slightly higher in the POD 1 group than in the POD 3 group (Table II).
Comparison of laboratory data between POD1 group and POD 3 group.
Of the three patients with POPF in the POD 1 group, one patient required drainage tube replacement because the drain fluid was turbid. In the two other patients, POPF became clinically significant after discharge, so readmission was required. Administration of antibiotics and somatostatin analogs cured the POPF without surgical drainage. Meanwhile, two patients with POPF in the POD 3 group required drainage tube replacement because of turbid drain fluid. The frequency of DGE did not differ significantly between the two groups [3.0% and 4.9%, respectively (p=0.617)].
Risk factors of POPF. DFA levels on POD 1 did not significantly differ between the POPF group and the non-POPF group. All patients with POPF had a POD 1 DFA ≥2,000 U/l, whereas no patients (0/28) with a POD 1 DFA <2,000 U/l developed it. WBC did not differ significantly between the two groups, whereas CRP was significantly higher in the POPF group than in the non-POPF group on POD 3 (p=0.003, Table III). The optimal cutoff level determined by ROC analysis was 18.7 mg/dl on POD 3, by which the value of the area under the curve (AUC) was 0.838. All five patients developing POPF had a CRP of 18.7 mg/dl or higher on POD 3; however, the specificity was moderate (66.0%). Similarly, CRP was significantly higher in the POPF group than in the non-POPF group on POD 5 (p<0.001). The optimal cutoff level determined was 16.6 mg/dl, by which the AUC value was 0.903 with 80% sensitivity and 95.1% specificity (Figure 1). One of the false-positive patients was with gastric perforation.
ROC curve based on C-reactive protein measured on postoperative day 5 in relation to postoperative pancreatic fistula after distal pancreatectomy. The optimal cutoff level was 16.6 mg/dl (AUC=0.903).
Comparison of laboratory data between POPF group and non-POPF group
Discussion
Drains are frequently placed after DP. However, the timing of drain removal is controversial. Being a risk factor for POPF, DFA is often used as a criterion of drain removal (1, 15-18, 21-24).
In previous reports, there have been situations where drains were not removed at POD 3 even if the DFA level was high (1, 15-18, 21, 24). Nevertheless, prolonged drain placement confers a risk of retrograde infection (13, 14) and ay contribute to POPF. Therefore, we routinely remove drains within POD 3 if the drain fluid is clear.
In our method, the incidence of POPF was only 4.6%. Of the five patients with POPF, three patients experienced turbid drain fluid on POD 3, whereas two patients have clear drain fluid. Therefore, predicting POPF not only by macroscopic findings but also by the use of laboratory data is necessary. In our data set, the DFA level on POD 1 was not a significant predictive factor. Although CRP on POD 3 was significantly higher in the POPF group than in the non-POPF group, the specificity was only 66.0%. Also, CRP on POD 5 was significantly higher in the POPF group, and the optimal cutoff level was 16.6 mg/dl. Sensitivity was 80%, and the specificity rose to 95.1%, which may be relatively effective as a predictor. To this end, it has been reported that CRP measured on POD 3 and POD 5 is effective as a predictor of post-PD POPF (25). Therefore, abdominal ultrasonography and CT might be considered for patients with high CRP on POD 5, and if POPF is suspected, treatment including antibiotics should be considered.
Recent reports have described that the rate of a positive drain culture (PDC) increased between POD 3 and POD 7 (13, 14, 26), and PDC has been associated with a higher incidence of abdominal complications, including POPF (13, 14, 26, 27). The occurrence of drain fluid contamination involves retrograde migration of bacteria along the drains (13, 14, 26). We also hypothesized that removing the drain earlier would reduce the chance of retrograde infection and reduce POPF and, thus, examined drain removal on POD 1. However, in this study, the rate of clinical POPF did not differ between POD 1 and POD 3 groups. We considered that this was because most of the patients in this study had their drains removed within 3 days after surgery, indicating a relatively good course.
Recent studies have described the usefulness of a POD 1 DFA of 2,000 U/l as a predictor of POPF (15-18). Considering our data, all patients with POPF had a POD 1 DFA ≥2,000 U/l, whereas no patients (0/28) with a POD 1 DFA <2,000 U/l developed it. However, sensitivity was 6.3%, suggesting that this cutoff level was difficult to use as a criterion for drain removal in our Institution.
Another issue concerning intraperitoneal drainage is the need for prophylactic intraperitoneal drainage. The elimination of routine intraoperative drainage has not been clearly associated with a statistically significant reduction of POPF (15, 28-31). Fluid collection (FC) is frequently observed in most patients after DP; however, most FC cases do not necessarily correlate with clinically relevant POPF or other abdominal complications (21, 32-34). The absence of FC infection appears to be an important factor to reduce the risk of clinically relevant POPF.
The limitations of this study include its retrospective nature, the fact that it was a single-center study, and the small number of POPF cases. However, our strategy of drain management may reduce the incidence of POPF. Furthermore, CRP of POD 3 and POD 5 appear to be useful as predictors of clinically relevant POPF.
Conclusion
There was no difference in the incidence of POPF between Day 1 group and Day 3 group. The timing of drain removal is controversial, but early drain removal regardless of the DFA level may reduce the incidence of POPF because the incidence of POPF was 4.6% in all cases. In our method, CRP on POD 3 and 5, especially POD 5 may be independent predictive factors of POPF.
Footnotes
Authors’ Contributions
All Authors helped to perform the research; Hiromichi Kawaida actively was involved in this study especially in statistical design. Concept and clinical design were conducted by six surgeons (Hiromichi Kawaida, Hiroshi Kono, Hidetake Amemiya, Naohiro Hosomura, Yuuki Nakata, Daisuke Ichikawa). Acquisition of data was done by all physicians (Hiromichi Kawaida, Hiroshi Kono, Hidetake Amemiya, Naohiro Hosomura, Yudai Higuchi, Takashi Nakayama, Isamu Tsukahara, Ryo Saito, Yuuki Nakata, Katsutoshi Shoda, Hiroki Shimizu, Shinji Furuya, Hidenori Akaike, Yoshihiko Kawaguchi, Makoto Sudo, Jun Itakura, Hideki Fujii, Daisuke Ichikawa). Interpretation of data and drafting the article were done by Hiromichi Kawaida. Finally, this article was revised and approved by all 18 investigators. Thus, all 18 Authors actively participated in this study.
Conflicts of Interest
Hiromichi Kawaida and the other co-authors declare that they have no conflicts of interest.
- Received August 18, 2020.
- Revision received November 27, 2020.
- Accepted December 4, 2020.
- Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
