Prone position increases the risk of pancreatic stula after laparoscopic radical gastrectomy combined with heated intraperitoneal chemotherapy: a case report

Background: There has not been reported that prone position increases the risk of postoperative pancreatic stula. We present a case of prone position leading to hyperthermia and pancreatic stula in a patient with acute respiratory distress syndrome(ARDS) after laparoscopic radical gastrectomy(LRG) combined with heated intraperitoneal chemotherapy(HIPEC). Case presentation: A 68-year-old male developed moderate ARDS after LRG combined with HIPEC. Since low tidal volume and high positive end expiratory pressure(PEEP) ventilation could not improve oxygenation, prone ventilation was selected to improve heterogeneous lung injury. However, chills and fever appeared after the position change. Abdominal computed tomography (CT) showed that the mesenteric fat space in the middle abdomen was fuzzy, local exudation was increased, and the boundary of pancreas was not clear. The increase of amylase in peritoneal drainage uid was 10 times higher than that in serum amylase. After communicating with the general surgeon, we learned that during the operation, the surgeon had opened the pancreatic capsule to clean the local lymph nodes. It was considered that prone position lead to the sharp increase of abdominal pressure, especially the change of peripancreatic pressure. The visceral organs of the abdominal cavity squeezed each other, the pancreatic tissue was compressed, the pancreatic juice extravasation occurred, and even aggravated the pancreatic stula. In the follow-up treatment process, the patient were given continuous abdominal drainage and avoided prone position as far as possible. Since then, the patient's temperature tended to be stable. On the 10th day after the operation, the patient successfully withdrew from the ventilator and transferred to the general ward for further specialized treatment. Conclusion: Our case adds further concerns in ARDS patients after LRG combined with HIPEC, including the monitoring postoperative pancreatic stula how to perform prone ventilation more safely.

low tidal volume and high positive end expiratory pressure(PEEP) ventilation could not improve oxygenation, prone ventilation was selected to improve heterogeneous lung injury. However, chills and fever appeared after the position change. Abdominal computed tomography (CT) showed that the mesenteric fat space in the middle abdomen was fuzzy, local exudation was increased, and the boundary of pancreas was not clear. The increase of amylase in peritoneal drainage uid was 10 times higher than that in serum amylase. After communicating with the general surgeon, we learned that during the operation, the surgeon had opened the pancreatic capsule to clean the local lymph nodes. It was considered that prone position lead to the sharp increase of abdominal pressure, especially the change of peripancreatic pressure. The visceral organs of the abdominal cavity squeezed each other, the pancreatic tissue was compressed, the pancreatic juice extravasation occurred, and even aggravated the pancreatic stula. In the follow-up treatment process, the patient were given continuous abdominal drainage and avoided prone position as far as possible. Since then, the patient's temperature tended to be stable. On the 10th day after the operation, the patient successfully withdrew from the ventilator and transferred to the general ward for further specialized treatment.
Conclusion: Our case adds further concerns in ARDS patients after LRG combined with HIPEC, including the monitoring of postoperative pancreatic stula and how to perform prone ventilation more safely.

Background
Laparoscopic radical gastrectomy(LRG) combined with heated intraperitoneal chemotherapy(HIPEC) is an effective treatment for advanced gastric cancer. Pancreatic stula and acute respiratory distress syndrome (ARDS) are common but serious complications. Prone ventilation has been used to improve oxygenation in patients with ARDS for a long time. It is crucial to determine whether prone position is associated or not with more pancreatic stula in patients with ARDS after abdominal surgery. In this paper, we present the case of prone position leading to hyperthermia and pancreatic stula in a patient with ARDS after LRG combined with HIPEC.

Case Presentation
A 68-year-old male presented to the digestive clinic with symptoms of fatigue for 6 months. He had no other symptoms before. The important past medical history were hypertension and coronary heart disease. After examination, he had anemia appearance, vital signs were stable, other general physical examination found no abnormality. Nerve, heart, lung and abdomen were normal. The BMI was 23.9 kg/m 2 . The chest and abdominal computed tomography (CT) showed no obvious abnormality.
( Fig. 1A,1D) Hemoglobin was 50 g/L and occult blood in stool was positive. Gastroscopy showed new organisms of ulcer in gastric horn and body, and pathological biopsy showed signet ring cell carcinoma. After proper communication and informed consent, LRG and HIPEC(0.9%normal saline 3500ml + 5uorouracil 1250mg,the input temperature was set to 43℃) were performed under general anesthesia.
After 30 minutes of HIPEC, the peritoneal drainage uid turned red. Considering the risk of bleeding, the hyperthermic perfusion therapy was terminated. The operation lasted for 5.5 hours, and the intraoperative blood loss was 100 ml. He had dyspnea, tachycardia(110-120 beats/min), high blood pressure(160/90 mmHg) and low oxygen saturation(88%) after extubation of endotracheal intubation.
The lung was scattered with moist rales, and the oxygenation index (OI) was 158.55 mmHg.
The chest CT was indicated patchy blurry shadows in both lungs and a small amount of bilateral pleural effusion ( Fig. 1B). According to 2011 Berlin ARDS diagnostic standard, he was diagnosed as moderate ARDS and then transferred to ICU for further intensive care.
In the rst two days after operation, he suffered from recurrent low fever and the body temperature uctuated from 36.5-38.1℃. Ceftazidime, famotidine and tranexamic acid were used. He were given noninvasive ventilator and invasive mechanical ventilation successively for protective lung ventilation strategy (low tidal volume, high frequency, high positive end expiratory pressure(PEEP)). However, the improvement of oxygenation was poor, and the lowest oxygenation index was 118.97 mmHg.
On the 3rd day after the operation, the patient was given prone position ventilation treatment. After 3 hours, the patient suddenly had chills, high fever, body temperature of 39.8 ℃, shortness of breath and decrease of blood oxygen saturation. The prone position was immediately suspended. The increase of interleukin-6, procalcitonin and C-reactive protein, and the decrease of lymphocytes were detected. Lung or abdominal infection was considered to be the main cause. Considering the history of malignant tumor, low immunity and high risk of drug-resistant bacteria infection, the antibiotic treatment was adjusted to imipenem cilastatin(1 g q8h).After that, the body temperature gradually decreased, and the oxygenation index increased to 422.14 mmHg. Because of the obvious improvement of oxygenation after prone position, the patient was given prone position ventilation again for 12.5 h at night. During this period, the patient's temperature uctuated between 37.5-38.8℃, without chills.
On the 4th day after operation, the body temperature uctuated from 36.8-37.6℃. The OIs were maintained above 200 mmHg, so the therapeutic schedule was not adjusted.
On the 5th day after operation, the patient was given prone position ventilation again because of the decrease of oxygenation index (110 mmHg). Two hours later, the prone position was suspended due to chills and high fever, and the body temperature rose to 39.2℃. At the same time, the patient presented mild abdominal muscle tension, upper abdominal tenderness, and the abdominal drainage volume increased signi cantly. There was no signi cant change in infection indicators. In order to exclude the occurrence of anastomotic leakage, the patient was given nasal feeding with a small amount of iodixanol, and chest and abdominal nonenhanced CT were performed (Fig. 1C,1E). Bilateral pleural effusion increased. Pulmonary infection remained substantially unchanged. CT image showed a massive leak of contrast agent to the esophagus, residual stomach and part of left small intestine. The pancreas was unclear contour. Under the electronic bronchoscope, white and viscous secretions were found in the dorsal segment of the left lower lobe, and a large number of watery secretions were found in bilateral bronchial lumens. Maltophilia oligomonas was cultured in bronchoalveolar lavage uid. According to the results of drug sensitivity, minocycline(0.1 g, q12h) was added for treatment. Amylase in peritoneal drainage uid was 1218 U/L (reference range: 0-300 U/L), serum amylase was 118.7 U/L (reference range: 35-135 U/L). Rivalta test was weakly positive. Lactate dehydrogenase in peritoneal drainage uid was 1103.9 U/L(reference range: 0-200 U/L). After communicating with the general surgeon, we learned that during the operation, the surgeon had opened the pancreatic capsule to clean the local lymph nodes. Therefore, we considered that the cause of high fever was that the pressure of abdominal cavity increases rapidly after prone position, which lead to the occurrence of pancreatic stula.
Therefore, in the follow-up treatment process, the patient were given continuous abdominal drainage and avoided prone position as far as possible. Since then, the patient's temperature tended to be stable. On the 10th day after the operation, the patient successfully withdrew from the ventilator and transferred to the general ward for further specialized treatment.

Discussion
ARDS is one of common pulmonary complications after radical gastrectomy. Prone position has been the most common therapeutic strategy to improve oxygenation in ARDS patients for a long time. Prone position demonstrated a strong survival bene t in patients with oxygenation index less than 150 mmHg [1]. Consistent with previous studies, oxygenation improved signi cantly after prone position in this case. Unfortunately, pancreatic stula occurred. The rst retrospective multicenter study evaluating the safety and e cacy of prone position in patients with severe ARDS after abdominal surgery, found that early postoperative prone position was not associated with increased local or surgical complications, and oxygenation improved signi cantly after one session of prone position [2]. However, the complications were limited to repercussions on scars, draining systems and stoma, not pancreatic stula.
Therefore, whether prone position in ARDS patients after total gastrectomy increases the risk of pancreatic stula remains to be further studied.
In 2016, the International Study Group rede ned postoperative pancreatic stula as drainage uid amylase concentration more than three times serum amylase concentration, and rede ned the classi cation. The "Grade A" pancreatic stula was rede ned as biochemical leakage, and only amylase in peritoneal drainage uid increased. "Grade B" was de ned as elevated pancreatic enzyme in drainage uid and clinical symptoms (fever, abdominal pain), which have an impact on the prognosis path, such as delayed indwelling of catheter, re placement of drainage tube, need for percutaneous puncture or endoscopic treatment of peritoneal effusion associated with pancreatic stula, and need for angiography or embolization for pancreatic stula related abdominal bleeding. Pancreatic stula was de ned as "Grade C" because of organ failure, reoperation and death [3].
Pancreatic stula is one of the most serious and potential complications after gastrectomy (4% − 6%) [4][5][6][7]. A national prospective cohort study in Japan has shown that the incidence of pancreatic stula after laparoscopic gastrectomy is higher than that of open surgery, which is associated with pressure and heat injury to the pancreas [8]. They developed a new laparoscopic method to avoid direct compression of the pancreas during suprapancreatic lymphadenectomy. During this process, the assistant pulls the connective tissue from the lower edge of the pancreas to the tail or back, instead of compressing the pancreas with gauze or sponge. This retrospective study con rmed that avoiding pancreatic pressure is one of the important methods to prevent pancreatic stula in laparoscopic distal gastrectomy [9]. Laparoscopic assisted surgery, combined organ resection, the use of LigaSure + ultrasonic scalpel and the number of lymph node dissection were independent in uencing factors of grade B pancreatic stula after radical gastrectomy for gastric cancer [10].
In this case, the expansion of the scope of lymph node dissection and pancreatic operation during laparoscopic surgery may lead to direct pancreatic injury. In addition, thermal injury during operation, including HIPEC, is also an important cause of pancreatic stula. HIPEC, a new adjuvant therapy, can kill tumor cells, inhibit DNA synthesis and destroy the metabolic growth of tumor cells by using the synergistic effect of hyperthermic cell thermal damage and chemotherapy drugs, effectively inhibit the growth of tumor cells after chemotherapy, and signi cantly reduce the local recurrence and distant metastasis rate of tumor patients. However, the high temperature of abdominal organs and the retention of chemotherapeutic drugs in the sunken part of abdominal cavity are high risk factors for systemic in ammatory response and ARDS.
The patient developed ARDS after the surgery. In the course of two times of prone position treatment, the patients had chills and high fever. It was considered that prone position leads to the increase of abdominal pressure, the mutual extrusion of abdominal organs and even aggravation of pancreatic stula.
Amylase concentration in drainage uid after gastric cancer surgery can be considered as an effective predictor of pancreatic related complications [7,11,12]. However, we did not realize to detect the amylase concentration in peritoneal drainage uid until the patients had abnormal symptoms after the therapeutic prone position, which indicated that we lacked prediction in the diagnosis and treatment of the disease. Whether the patient had a biochemical leak prior to prone position or not was unknown.
Therefore, whether the amylase concentration in the drainage uid on the rst day after gastric cancer surgery can be used as a useful potential risk factor for pancreatic related complications needs further study.

Conclusion
Page 6/8 The management of patients with large-scale abdominal surgery needs multidisciplinary cooperation. Surgeons should be gentle, maintain the intact pancreatic capsule as far as possible, and minimize pancreatic injury during operation. We should consider the advantages and disadvantages of HIPEC in patients with abdominal tumor resection, and pay more attention to the stimulation of temperature and chemotherapy drugs on abdominal organs. Critical physicians need to be fully aware of the details of the operation and should be circumspect to choose prone position ventilation strategy in the treatment of perioperative ARDS patients. If it is unavoidable to choose prone position ventilation in order to improve the body's hypoxia and oxygenation index, we can try to pad swimming circle around the abdomen and expose the position of abdominal median incision or internal organs to relieve abdominal visceral extrusion (Fig. 2). Meanwhile, we should closely monitor the changes of vital signs and the uctuation of amylase in drainage uid and serum.