Risk Factors and Causes of Fever after Endoscopic Submucosal Dissection

doi:10.21203/rs.3.rs-494719/v1

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Risk Factors and Causes of Fever after Endoscopic Submucosal Dissection

https://doi.org/10.21203/rs.3.rs-494719/v1

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Background To investigate the fever and related risk factors of gastrointestinal mucosa or submucosal lesions after endoscopic mucosal dissection(ESD).

Method A retrospective analysis of patients undergoing ESD. Patients were divided into two groups according to the presence or absence of post-ESD fever. Patient-related factors and lesion-related factors were counted in both groups.

Results The incidence of fever was 31.0% in 290 patients after the operation, 87 patients developed fever within 24 hours after operation. The average of (2.82 ± 1.186) days. According to logistic analysis, the surgical site was in the esophagus (OR value: 6.439; 95% CI: 2.030-20.424; P value: 0.002), with diabetes history (OR value: 3.289; 95% CI: 1.015-10.662; P value: 0.047), age≥70.6 years (OR value: 0.844; 95% CI: 0.805-0.884; P value: 0.000), resection diameter> 4.25 mm (OR value: 2.361; 95% CI: 5.202-29.371; P value: 0.000), operation time> 196min (OR value: 1.022; 95% CI: 1.003-1.042; P value: 0.022) were risk factors for fever.

Conclusions Older patient, the operation site in esophagus, diabetes, large tumors and long operation time were more likely to develop post-ESD fever, The possibility of bacteremia after ESD is small, antibiotics do not need to be applied in advance.

Oncology

Endoscopic submucosal dissection (ESD)

post-ESD fever

complication

In recent years, endoscopic submucosal dissection (ESD) has been used as a common endoscopic treatment for early gastrointestinal cancer, precancerous lesions and submucosal lesions. Postoperative fever is one of the common complications. However, there are few systematic data on the causes and treatment of postoperative fever after ESD. There is no consensus on whether the preventive use of antibiotics can reduce the incidence of postoperative fever and pneumonia. In this study, the risk factors and causes of fever after ESD were analyzed by statistics of patient-related factors and disease-related factors, in order to better help the understanding and treatment of fever after ESD.

Patients and methods

This article is a retrospective study that collected a total of 290 cases of ESD from the same senior endoscopy physician in Shandong Cancer Hospital from July 1, 2018 to July 1, 2019. Before this study, the physician had performed ESD surgery in over 100 cases and was proficient in operation. Postoperative fever refers to the BT of the patient after ESD ≥ 37.8℃. According to whether there was post-ESD fever, the patients were divided into the following two groups: group A, BT ≥ 37.8 ° C; group B, BT < 37.8 ° C.

Preoperative preparation

All patients signed the ethical informed consent, then underwent routine clinical examination after admission, including blood routine, urine routine, coagulation function, electrocardiogram, and enhanced CT of lesion site. Patients with hypertension and diabetes should be operated on when their condition is basically stable. Informed consent and surgical consent should be signed before operation. oral temperature was measured 2 hours before the operation, those whose BT was higher than 37.8 ° C,the operation was suspended to find out the cause of fever.

ESD treatment

Esophageal and gastric ESD was performed using Olympus Q260J electronic gastroscope; Colorectal ESD was performed using Olympus Q260JI electronic colonoscopy; high-frequency generator: VIO200D,ERBE, Elektromedizin, Germany; DualKnife: Olympus, Japan. KD-650Q knife for esophageal lesions; KD-650L knife for gastric lesions; KD-650U knife for colorectal lesions; hemostatic forceps: FD-411UR, Olympus, Japan; hemostatic clips: ROCC-D-26-195, Micro-Tech Co, China.

The upper gastrointestinal ESD surgery was performed under general anesthesia with tracheal intubation, and the catheter was inserted before operation. The lower gastrointestinal ESD surgery was performed under awake state without catheter. Blood oxygen saturation monitoring and electrocardiographic monitoring were performed in all patients during the entire operation and 24 hours after the operation.

(1) NBI or chromoendoscopy staining was used to determine the lesion range, such as 1.2% compound iodine solution was sprayed for esophageal mucosal lesions, 0.4% indigo carmine was sprayed for gastric and colorectal mucosal lesions to help to determine the lesion range;(2) DualKnife was used to electrocoagulate the lesion range at a distance of 5mm from the peripheral edge of the lesion, with an interval of 5mm between each marker point;(3) 4% methylene blue glycerin fructose mixture was used for multi-point submucosal injection on the outside of the marked range to raise the lesion and separate it from the muscularis propria;(4) The mucosa was cut with DualKnife along the peripheral marks of the lesion, and then the submucosa is peeled off step by step;(5) After the entire specimen is resected, the exposed vessels of the wound surface and wound margin were prevented from hemostasis by electric hemostatic forceps or hemostatic clips. The post-operative resection specimens were fixed on the foam plate with pins, marked the oral and anal sides, and immersed in 10% formalin solution. The time from the beginning of the peripheral markers to the end of preventive hemostasis after ESD was named as the operating time of ESD.

Complication

Common complications of ESD include bleeding and perforation. Pneumonia refers to the new pulmonary infiltration, consolidation or pleural effusion found in chest CT examination compared to preoperative examination[1].

Pathology

The lesion size, site, histological type, depth of infiltration, degree of differentiation, horizontal and vertical margins, and presence or absence of vascular and lymphatic infiltration were recorded. The lesion length was measured on the specimen after ESD surgery, and the longest diameter of the lesion was taken as the length of the lesion.

Postoperative management

After upper gastrointestinal tract ESD, gastrointestinal decompression tube was placed, fasting and water prohibited, acid suppression and gastric mucosal protection drugs were applied intravenously. If there is no perforation or massive bleeding, no matter whether there was fever, patients began to drink water and eat soft food 3 days after ESD. Fasting and water deprivation on the first day after ESD of lower digestive tract, and began to drink water and eat soft food on the day after operation.

After surgery all patients measured their body temperature at 8:00, 12:00, 16:00 and 20:00 to 72h, the second day after ESD check all cases of blood routine and urine routine to evaluate the inflammatory reaction. If the patient's body temperature increased, blood culture and chest CT were carried out. According to the body temperature, peripheral blood examination, lung breathing sound, blood culture results and chest CT examination determined whether the fever patient had infection and needed antibiotics. If there is no evidence of infection, antibiotics would not be given, physical cooling method or antipyresis is given to oral temperatures above 38.5° C, If there is evidence of infection, antibiotics will be given according to the blood culture results or experience, and record whether the patient has any other discomfort symptoms, such as pain, amount of drainage fluid, delayed bleeding and delayed perforation.

Follow up

Gastroscopy was performed at 3, 6, and 12 months after surgery, and once a year thereafter. Take a combination of outpatient follow-up and telephone follow-up.

Statistical analysis

All data were analyzed by SPSS 20.0. The measurement data were expressed as median (minimum, maximum) and were compared by Mann-Whitney U test.χ2 or Fisher test was used to compare the differences in the categorical variables between groups. Univariate analysis regression was used to analyze the risk factors of fever after ESD, and the ratio of each factor to fever (OR) and 95% confidence interval were calculated. Cutoff points of continuous variables were detected by ROC curve analysis. Calculate the optimal Cutoff value using the Jordan index. P < 0.05 was considered statistically significant.

As shown in Table 1, there were no significant differences between the two groups in terms of gender, history of hypertension, smoking, drinking, BMI and depth of lesion infiltration (P > 0.05), while there were statistically significant differences in age and diabetes.

Table 1

Comparison of cases with fever team and no fever team after ESD.
	A team(n = 90)	B team(n = 200)	P
Gender (Male: Female)	46:44	108:92	0.492
Age (years)	70.6(36–83)	62(35–84)	0.049
Lesion (esophagus: stomach: intestine)	38:48:4	34:144:22	0.000
BMI(kg/㎡)	22.40	21.87	0.570
History of hypertension	26(28.9%)	54(27.0%)	0.514
History of diabetes	7(7.8%)	5(2.5%)	0.000
smoking	14(15.6%)	44(22%)	0.197
Drinking	31(34.4%)	63(31.5%)	0.018
Lesion size (cm)	6.3	3.27	0.000
Operation time (min)	195.78	106	0.000

The frequency of fever was different in different location (P = 0.000 < 0.05), as shown in Fig. 1. The incidence of esophageal ESD postoperative fever is 52.8%, gastric ESD postoperative fever is 25%, and colorectal ESD postoperative fever is 15.4%.

The average operation time in group A was 195.8 minutes (100–320 minutes), which was significantly longer than that in group B (106 − 20 minutes) (30-2010 minutes) (P = 0.000 < 0.05). The size of the lesions in group A was 6.3 cm, which was significantly higher than group B 3.27cm (1.5-6.0cm) (P = 0.000 < 0.05);

Logistic analysis of the risk factors of post-ESD fever is shown in Table 2. Gender, smoking, hypertension and infiltration depth of lesions were not risk factors for fever; age, diabetes, operation time, lesion size and operation location(figure 2) were risk factors for fever after ESD operation.

Table 2

Logistic analysis of the risk factors of postoperative fever of ESD.
	OR	95%CI	P
gender	1.862	0.343–10.105	0.471
age	1.185	1.131–1.242	0.000
Lesion	0.116	0.030–0.444	0.002
BMI	1.202	0.938–1.540	0.145
hypertension	1.679	0.319–8.843	0.541
diabetes	3.289	1.015–10.662	0.047
Smoking	0.405	0.039–4.248	0.451
Drinking	0.763	0.155–3.768	0.740
Lesion size	12.361	5.202–29.371	0.000
operation time	1.022	1.003–1.042	0.022
Infiltration depth	1.494	0.385–5.795	0.562
pathology	1.211	0.417–3.517	0.725

In group A, oral temperature was between 37.5 ° C -39.6 ° C, with an average of (38.3 ± 0.53) ℃, and the duration of fever was 1-7d, with an average of (2.82 ± 1.186) d. 77 patients had normal blood and normal urine, no urinary tract infection, cough and sputum, and negative blood culture; 8 patients had increased in leukocyte (> 10 × 109 / L) and proportion of neutrophils (> 70%), no urinary tract infection, cough and sputum, negative blood culture, normal chest CT and urinalysis, no antibiotics were given, only physical cooling or antipyretic treatment when the oral temperature was over 38.5 ℃, all patients could drop to normal body temperature after 1–3 days; 5 patients had normal urine routine, increased leukocyte (> 10 × 109 / L)and neutrophil ratio (> 70%), they had clinical symptoms of lung infection, such as cough and sputum, chest CT showed pneumonia, blood culture was positive in one case, they were confirmed as pneumonia, all of them were elderly patients with esophageal disease (age ≥ 70.6 years). Urine routine was normal in all patients with fever, and blood culture was positive in one case(Table 3).

Table 3

Situation of patients with pneumonia after ESD.
Number of pneumonia	5
Gender: Male Female)	1:4
age)	73 ± 2.345
Location (esophagus: stomach: intestine)	5:0:0
BMI (kg/㎡)	23(20–26)
History of hypertension	3
History of diabetes	1
Smoking	2
Drinking	2
Lesion size (cm)	5.7 ± 1.681
Operation time (min)	234 ± 67.676
Duration of fever	6.2 ± 0.837
Sedation method	General Anesthesia for tracheal intubation

Surgical fever is very common after open surgery[2], which is one of the host responses to surgery[3]. Postoperative fever is most commonly attributed to noninfectious causes. It is associated with the normal thermoregulatory response without infection in vivo. It is most commonly caused by inflammatory changes from the release of pyrogenic cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor, and interferon-r[4]. The cytokines act directly on the anterior hypothalamus and cause a release of prostaglandins, which mediate the febrile response inflammation secondary to cytokine release [5]. Except for postoperative pain and discomfort, patients may have changes in blood routine, no abnormality in chest CT. In this study, the incidence of fever in all ESD postoperative patients was 33.7% (33/98).Compared with the conventional ulcer, the ulcer after ESD is formed in a short period of time and the ulcer infiltrates deeper, it suffers from more invasive injury in a short period of time, such as electrocoagulation or electrotomy for cutting or hemostasis, which inevitably contact with muscularis propria, leading to inflammation or fever.

Another common hospital infection is urinary tract infection, which is mostly caused by long-term indwelling catheter or unsatisfactory aseptic operation during catheterization and improper perineal care[6]. Bacteria can retrograde along the urethra and develop cystitis and even pyelonephritis. Our preventive measures are as follows: (1) Catheter insertion should be strictly sterile, daily wiping and washing the perineum with 0.05% iodine solution. colorectal ESD was performed soberly, and no catheter was placed. (2) Catheter removal as soon as possible to shorten the indwelling time, generally not more than 24 hours. The results of the above measures were satisfactory, 290 patients had no urinary tract infection.

This study also found that the incidence of pneumonia in elderly patients increased significantly,on the other hand, elderly patients may differ from younger patients in several ways, including the number and severity of comorbid conditions they have[7]. As the population ages, issues related to the surgical care of elderly patients are becoming increasingly common[8]. Understanding the perioperative factors associated with adverse outcomes can allow for identification of at-risk patients to allow for development of tailored preventative strategies and resource planning to decrease the complications elderly surgical patients[9].

During the ESD, injection needle catheter is passed through the contaminated endoscopic channel and may directly inoculate bacteria into the blood stream during submucosal injection[10]. In addition, ESD can produce mucosal defects, which are open without closure, submucosal and muscularis propria exposuring to native bacterial flora in the gastrointestinal tract may lead to bacteremia and / or endotoxemia[11, 12, 13]. We performed blood culture on each patient with post-ESD fever, only 1 patients had positive blood culture. Kawata et al.[14] observed a similar situation: They performed blood culture immediately on 101 post-ESD patients, 7 of whom were positive, and only 1 of them was positive on the second day after operation. None of the 10 patients whose body temperature > 38℃ showed positive blood culture. The reasons were analyzed as follows[15]: (1) the postoperative infection was limited, and bacteria did not enter the systemic circulation; (2) blood collection time is not in the time of bacteria entering the blood flow. There are no clear guidance on whether to use antibiotics routinely after ESD, according to recent guidelines for gastroenteroscopy in the United States, antibiotics are not necessary to prevent fever and pneumonia, American Society of Gastroenterology (ASGE) and British Society of Gastroenterology (BSG) guidelines[16, 17, 18] only recommend prophylactic antibiotics for ERCP, ileostomy, variceal ligation in digestive endoscopy. Our study found that patients after ESD may show some inflammatory manifestations, but the possibility of bacteremia is small, the positive rate of blood culture in post-ESD fever patients is low, which is not recommended. However, There were other studies that were contrary to this, they reported that prophylactic antibiotics before and after surgery can reduce the incidence of fever and pneumonia [19, 20]. In this study, not every patient underwent surgical blood culture,the infection status may be biased, statistics on this aspect need to be improved in the next prospective study[21].

The difficulty of ESD operation in different parts is different, which is related to the operator's operation level and experience. This study was performed by the same surgeon, who was skilled in this kind of operation, so the latter factor was excluded. We found that the probability of fever in different parts of the digestive tract was different. The probability of post-ESD fever in esophagus and stomach was higher than that in the colorectal. The reasons are analyzed: the esophageal wall is relatively thin, the operation space is small, it is more easily to cause perforation, and then may cause pneumothorax and mediastinum infection; pump water may needed to flush the wound surface during operation, the possibility of misinhalation and aspiration pneumonia increased, may lead to fever. Our findings show that the probability of post-ESD fever in colorectal is lower than that of stomach, which is different from some previous studies[22, 23]. The reasons are analyzed:(1) In order to reduce the chance of perforation, bleeding and infection, most of the wounds after colorectal surgery are closed with metal clips, unless the wounds are too large to occuring intestinal stenosis if metal clips are closed. (2) In this study, colorectal ESD was performed in conscious state, the recovery of body state was faster after operation, aspiration under anesthesia was avoided. (3) The colorectal sample was small in this study.

By ROC curve analysis, we found that the lesion size > 4.25cm was a predictor of post-ESD fever. The operation requires a longer duration, the contact time between the electrosurgical knife and the submucosa is also extended, mechanical injury to the tissue increases. It is suggested that for patients with large specimens or complicated lesion, we should be alert to postoperative fever, intervene and prevent it early[24].

Patients with diabetes in this study had a higher incidence of fever after ESD. which may be related to the deficiency of immune functions, cell chemotaxis and phagocytosis, and intracellular sterilization and other defense functions, polymorphonuclear leukocyte function is depressed, particularly when acidosis is also present. Leukocyte adherence, chemotaxis, and phagocytosis may be affected[25, 26]. There is evidence that improving glycemic control in patients can improve immune function, the efficiency of intracellular killing of microorganisms may improve with better glycemic control. It is suggested that the blood glucose level should be controlled well perioperative ESD, the dosage of insulin should be adjusted reasonably according to the specific conditions of patients[27].

In conclusion, our study showed that the operation site in esophagus, diabetes history, age over 70.6 years old, resection diameter > 4.25 mm, operation time > 196min were risk factors of fever. Therefore, special attention should be paid to patients with these risk factors. As for the diagnosis of pneumonia, doctors should consider whether to carry out CT according to the situation of postoperative patients, not every patient is examined after operation, so there may be missed diagnosis. The research results need to be verified by a larger sample study. Different anesthesia methods and drugs may influence the occurrence of postoperative pneumonia, and pneumonia is one of the main causes of fever, so the relationship between anesthesia and fever needs further study.

Ethics approval and consent to participate

The study was approved by the ethics committee of the Shandong Cancer Hospital Affiliated to Shandong University（# SDTHEC201806067, June 2018） and was conducted in accordance with the revised Helsinki Declaration (2013), individual consent for this retrospective analysis was waived.

Consent for publication Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported in part by the Jinan Science and Technology Bureau(CN) (202019039) and National Key Research and Development Program(CN) (2018YFC0114707).

Authors’ Contribution

Ming Chen: M.D. E-mail: [email protected], conceived and designed the experiments;

Jinqi Liu: M.B. E-mail:[email protected], performed the data collection;

Xiaoxue Zhang：M.B. E-mail:[email protected], performed the data analysis and interpretation；

Dongyang Wang: M.D. E-mail: [email protected], performed the data collection;

Haipeng Wang: M.M. E-mail: [email protected], performed the data analysis and interpretation；

Guangfeng Dong: M.M. E-mail: [email protected], performed the manuscript preparation;

Huizhuan Zhai: M.B. E-mail: [email protected], performed the writing revision and modifications of figures. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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Risk Factors and Causes of Fever after Endoscopic Submucosal Dissection

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Version 1

Abstract

Figures

Introduction

Materials And Methods

Patients and methods

Preoperative preparation

ESD treatment

Complication

Pathology

Postoperative management

Follow up

Statistical analysis

Result

Discussion

Declarations

Ethics approval and consent to participate

Competing interests

References

Status:

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